chr17-63918770-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000515.5(GH1):c.7A>C(p.Thr3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,613,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T3A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

GH1
NM_000515.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.06

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 links:

ENSG00000285947 (HGNC:):

ENSG00000285947 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024536937).

BP6

Variant 17-63918770-T-G is Benign according to our data. Variant chr17-63918770-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 452376.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000394 (60/152284) while in subpopulation NFE AF = 0.000529 (36/68014). AF 95% confidence interval is 0.000392. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GH1	NM_000515.5 link	c.7A>C	p.Thr3Pro	missense_variant	Exon 1 of 5	ENST00000323322.10	NP_000506.2	P01241-1B1A4G6
GH1	NM_022559.4 link	c.7A>C	p.Thr3Pro	missense_variant	Exon 1 of 5		NP_072053.1	P01241-2B1A4G7
GH1	NM_022560.4 link	c.7A>C	p.Thr3Pro	missense_variant	Exon 1 of 4		NP_072054.1	P01241-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GH1	ENST00000323322.10 link	c.7A>C	p.Thr3Pro	missense_variant	Exon 1 of 5	1	NM_000515.5	ENSP00000312673.5		P01241-1
ENSG00000285947	ENST00000647774.1 link	c.287-264A>C		intron_variant	Intron 4 of 7			ENSP00000497443.1		A0A3B3ISS9

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000232

AC:

AN:

249884

AF XY:

0.000222

show subpopulations

Gnomad AFR exome

AF:

0.000254

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.000200

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000301

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000269

AC:

393

AN:

1460778

Hom.:

Cov.:

AF XY:

0.000263

AC XY:

191

AN XY:

726758

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

AC:

AN:

33422

Gnomad4 AMR exome

AF:

0.000179

AC:

AN:

44710

Gnomad4 ASJ exome

AF:

0.0000383

AC:

AN:

26128

Gnomad4 EAS exome

AF:

0.000504

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.000209

AC:

AN:

86236

Gnomad4 FIN exome

AF:

0.0000936

AC:

AN:

53420

Gnomad4 NFE exome

AF:

0.000283

AC:

314

AN:

1111062

Gnomad4 Remaining exome

AF:

0.000315

AC:

AN:

60348

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome 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

GnomAD4 genome

AF:

0.000394

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000457

AC:

0.000457457

AN:

0.000457457

Gnomad4 AMR

AF:

0.0000654

AC:

0.0000653509

AN:

0.0000653509

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000193

AC:

0.000192827

AN:

0.000192827

Gnomad4 SAS

AF:

0.000207

AC:

0.000206954

AN:

0.000206954

Gnomad4 FIN

AF:

0.0000941

AC:

0.0000941088

AN:

0.0000941088

Gnomad4 NFE

AF:

0.000529

AC:

0.000529303

AN:

0.000529303

Gnomad4 OTH

AF:

0.000473

AC:

0.00047259

AN:

0.00047259

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.000119

Hom.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Oct 23, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The T3P variant in the GH1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is observed in 10/23,584 alleles (0.042%) from individuals of African background and 10/34,282 alleles (0.029%) from individuals of Latino background, with one homozygous control individual reported, in the gnomAD dataset (Lek et al., 2016). The T3P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. We interpret T3P as a variant of uncertain significance. -

not specified

Benign:1

Dec 22, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GH1 c.7A>C (p.Thr3Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 249884 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in GH1 causing Idiopathic Growth Hormone Deficiency phenotype (6.3e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.7A>C in individuals affected with Idiopathic Growth Hormone Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17223997, 18950677). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.35

CADD

Benign

1.8

DANN

Benign

0.32

DEOGEN2

Benign

0.072

.;.;.;T;T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.49

T;T;T;T;T;.

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.025

T;T;T;T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

-0.81

.;N;N;N;.;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.55

N;N;N;N;N;.

REVEL

Uncertain

0.33

Sift

Benign

0.65

T;T;T;T;T;.

Sift4G

Benign

0.26

T;T;T;T;T;D

Polyphen

0.0, 0.026, 0.044

.;.;.;B;B;B

Vest4

0.19

MVP

0.22

MPC

0.14

ClinPred

0.0013

GERP RS

-0.16

Varity_R

0.10

gMVP

0.23

Mutation Taster

=97/3

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over