chr17-63918770-T-C

Position:

chr17-63918770-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000515.5(GH1):c.7A>G(p.Thr3Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,607,952 control chromosomes in the GnomAD database, including 537 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 222 hom., cov: 32)

Exomes 𝑓: 0.012 ( 315 hom. )

Consequence

GH1
NM_000515.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017983615).

BP6

Variant 17-63918770-T-C is Benign according to our data. Variant chr17-63918770-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 289503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63918770-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GH1	NM_000515.5 linkuse as main transcript	c.7A>G	p.Thr3Ala	missense_variant	1/5	ENST00000323322.10	NP_000506.2
GH1	NM_022559.4 linkuse as main transcript	c.7A>G	p.Thr3Ala	missense_variant	1/5		NP_072053.1
GH1	NM_022560.4 linkuse as main transcript	c.7A>G	p.Thr3Ala	missense_variant	1/4		NP_072054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GH1	ENST00000323322.10 linkuse as main transcript	c.7A>G	p.Thr3Ala	missense_variant	1/5	1	NM_000515.5	ENSP00000312673	P1	P01241-1

Frequencies

GnomAD3 genomes

AF:

0.0352

AC:

5353

AN:

152126

Hom.:

222

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0952

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0188

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.0319

Gnomad SAS

AF:

0.00724

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.0253

GnomAD3 exomes

AF:

0.0143

AC:

3583

AN:

249884

Hom.:

AF XY:

0.0130

AC XY:

1751

AN XY:

135138

show subpopulations

Gnomad AFR exome

AF:

0.0829

Gnomad AMR exome

AF:

0.0107

Gnomad ASJ exome

AF:

0.00918

Gnomad EAS exome

AF:

0.0271

Gnomad SAS exome

AF:

0.00593

Gnomad FIN exome

AF:

0.00153

Gnomad NFE exome

AF:

0.00919

Gnomad OTH exome

AF:

0.0106

GnomAD4 exome

AF:

0.0118

AC:

17209

AN:

1455708

Hom.:

315

Cov.:

AF XY:

0.0115

AC XY:

8325

AN XY:

724374

show subpopulations

Gnomad4 AFR exome

AF:

0.0853

Gnomad4 AMR exome

AF:

0.0123

Gnomad4 ASJ exome

AF:

0.00989

Gnomad4 EAS exome

AF:

0.0297

Gnomad4 SAS exome

AF:

0.00625

Gnomad4 FIN exome

AF:

0.00174

Gnomad4 NFE exome

AF:

0.00979

Gnomad4 OTH exome

AF:

0.0144

GnomAD4 genome

AF:

0.0352

AC:

5356

AN:

152244

Hom.:

222

Cov.:

AF XY:

0.0343

AC XY:

2552

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0950

Gnomad4 AMR

AF:

0.0188

Gnomad4 ASJ

AF:

0.0107

Gnomad4 EAS

AF:

0.0320

Gnomad4 SAS

AF:

0.00745

Gnomad4 FIN

AF:

0.00188

Gnomad4 NFE

AF:

0.0118

Gnomad4 OTH

AF:

0.0246

Alfa

AF:

0.00745

Hom.:

Bravo

AF:

0.0392

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.0765

AC:

337

ESP6500EA

AF:

0.00942

AC:

ExAC

AF:

0.0184

AC:

2230

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 11, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 27, 2016

- -

Autosomal dominant isolated somatotropin deficiency;C0342573:Ateleiotic dwarfism;C1849779:Short stature due to growth hormone qualitative anomaly;C2748571:Isolated growth hormone deficiency type IB

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 29, 2017

- -

Decreased response to growth hormone stimulation test

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.035

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.11

DANN

Benign

0.13

DEOGEN2

Benign

0.069

.;.;.;T;T;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0054

LIST_S2

Benign

0.53

T;T;T;T;T;.

MetaRNN

Benign

0.0017

T;T;T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

-1.6

.;N;N;N;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.47

PROVEAN

Benign

1.7

N;N;N;N;N;.

REVEL

Benign

0.27

Sift

Benign

1.0

T;T;T;T;T;.

Sift4G

Benign

1.0

T;T;T;T;T;D

Polyphen

0.0

.;.;.;B;B;B

Vest4

0.036

MPC

0.10

ClinPred

0.00032

GERP RS

-0.16

Varity_R

0.036

gMVP

0.21

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