chr17-63917428-C-G

Position:

chr17-63917428-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_000515.5(GH1):c.535G>C(p.Asp179His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000345 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

GH1
NM_000515.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.46

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:

LOC112268204 (HGNC:):

LOC112268204 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13372788).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000204 (31/152278) while in subpopulation NFE AF= 0.000368 (25/68026). AF 95% confidence interval is 0.000255. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GH1	NM_000515.5 linkuse as main transcript	c.535G>C	p.Asp179His	missense_variant	5/5	ENST00000323322.10
LOC112268204	XR_002958148.2 linkuse as main transcript	n.341-169C>G		intron_variant, non_coding_transcript_variant
GH1	NM_022559.4 linkuse as main transcript	c.490G>C	p.Asp164His	missense_variant	5/5
GH1	NM_022560.4 linkuse as main transcript	c.415G>C	p.Asp139His	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GH1	ENST00000323322.10 linkuse as main transcript	c.535G>C	p.Asp179His	missense_variant	5/5	1	NM_000515.5	P1	P01241-1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000131

AC:

AN:

251168

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000264

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000360

AC:

526

AN:

1461674

Hom.:

Cov.:

AF XY:

0.000355

AC XY:

258

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000444

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000204

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000268

Hom.:

Bravo

AF:

0.000212

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 15, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects GH1 function (PMID: 18785993). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 891323). This missense change has been observed in individual(s) with autosomal dominant growth hormone deficiency (PMID: 18785993). This variant is present in population databases (rs151243538, gnomAD 0.02%). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 179 of the GH1 protein (p.Asp179His). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2022	Identified in the heterozygous state in one individual with partial IGHD, but segregation data is limited (de Graaff et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(D153H); This variant is associated with the following publications: (PMID: 18785993) -

Decreased response to growth hormone stimulation test

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.28

CADD

Benign

6.0

DANN

Benign

0.26

DEOGEN2

Pathogenic

0.84

.;.;D;D

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.71

T;T;T;T

M_CAP

Uncertain

0.090

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-0.39

MutationTaster

Benign

0.56

D;N;N;N;N

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.4

D;D;D;D

REVEL

Benign

0.28

Sift

Benign

0.16

T;T;T;T

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.014, 0.0040

.;.;B;B

Vest4

0.15

MVP

0.65

MPC

0.16

ClinPred

0.024

GERP RS

-2.4

Varity_R

0.27

gMVP

0.45

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