17-63917810-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000515.5(GH1):c.406G>A(p.Val136Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00762 in 1,614,182 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0052 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0079 ( 44 hom. )

Consequence

GH1
NM_000515.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.804

Publications

20 publications found

Variant links:

Genes affected

GH1 (HGNC:4261): (growth hormone 1) The protein encoded by this gene is a member of the somatotropin/prolactin family of hormones which play an important role in growth control. The gene, along with four other related genes, is located at the growth hormone locus on chromosome 17 where they are interspersed in the same transcriptional orientation; an arrangement which is thought to have evolved by a series of gene duplications. The five genes share a remarkably high degree of sequence identity. Alternative splicing generates additional isoforms of each of the five growth hormones, leading to further diversity and potential for specialization. This particular family member is expressed in the pituitary but not in placental tissue as is the case for the other four genes in the growth hormone locus. Mutations in or deletions of the gene lead to growth hormone deficiency and short stature. [provided by RefSeq, Jul 2008]

GH1 Gene-Disease associations (from GenCC):

isolated growth hormone deficiency type IA
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
isolated growth hormone deficiency type II
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
isolated growth hormone deficiency type IB
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
short stature due to growth hormone qualitative anomaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GH1 links:

ENSG00000285947 (HGNC:):

ENSG00000285947 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM1

In a disulfide_bond (size 112) in uniprot entity SOMA_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_000515.5

BP4

Computational evidence support a benign effect (MetaRNN=0.028960973).

BP6

Variant 17-63917810-C-T is Benign according to our data. Variant chr17-63917810-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 197151. Variant chr17-63917810-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 197151. Variant chr17-63917810-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 197151. Variant chr17-63917810-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 197151. Variant chr17-63917810-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 197151. Variant chr17-63917810-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 197151. Variant chr17-63917810-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 197151. Variant chr17-63917810-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 197151. Variant chr17-63917810-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 197151.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00523 (797/152292) while in subpopulation NFE AF = 0.00876 (596/68032). AF 95% confidence interval is 0.00818. There are 3 homozygotes in GnomAd4. There are 335 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GH1	NM_000515.5 link	c.406G>A	p.Val136Ile	missense_variant	Exon 4 of 5	ENST00000323322.10	NP_000506.2	P01241-1B1A4G6
GH1	NM_022559.4 link	c.361G>A	p.Val121Ile	missense_variant	Exon 4 of 5		NP_072053.1	P01241-2B1A4G7
GH1	NM_022560.4 link	c.286G>A	p.Val96Ile	missense_variant	Exon 3 of 4		NP_072054.1	P01241-5
LOC112268204	XR_002958148.2 link	n.409C>T		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GH1	ENST00000323322.10 link	c.406G>A	p.Val136Ile	missense_variant	Exon 4 of 5	1	NM_000515.5	ENSP00000312673.5		P01241-1
ENSG00000285947	ENST00000647774.1 link	c.682G>A	p.Val228Ile	missense_variant	Exon 7 of 8			ENSP00000497443.1		A0A3B3ISS9

Frequencies

GnomAD3 genomes

AF:

0.00523

AC:

796

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00186

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00876

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00571

AC:

1436

AN:

251450

AF XY:

0.00540

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00743

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00305

Gnomad NFE exome

AF:

0.00892

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00787

AC:

11506

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00753

AC XY:

5478

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00152

AC:

AN:

33478

American (AMR)

AF:

0.00698

AC:

312

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00302

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000301

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00335

AC:

179

AN:

53420

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00941

AC:

10467

AN:

1112012

Other (OTH)

AF:

0.00634

AC:

383

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

882

1764

2646

3528

4410

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

394

788

1182

1576

1970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00523

AC:

797

AN:

152292

Hom.:

Cov.:

AF XY:

0.00450

AC XY:

335

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

41570

American (AMR)

AF:

0.00431

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5170

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00273

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00876

AC:

596

AN:

68032

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

133

177

221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00758

Hom.:

Bravo

AF:

0.00561

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0101

AC:

ExAC

AF:

0.00545

AC:

662

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00894

EpiControl

AF:

0.00895

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GH1: PM5, BP4, BS2 -

Decreased response to growth hormone stimulation test

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:1

Mar 30, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.35

.;.;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.73

T;T;T

MetaRNN

Benign

0.029

T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

0.39

.;.;N

PhyloP100

0.80

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.40

N;N;N

REVEL

Benign

0.23

Sift

Benign

0.21

T;T;T

Sift4G

Benign

0.50

T;T;T

Polyphen

0.0020

.;.;B

Vest4

0.11

MVP

0.64

MPC

0.084

ClinPred

0.0042

GERP RS

2.9

Varity_R

0.12

gMVP

0.35

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over