rs4988496

Variant names:

• chr7-30969071-G-A
• rs4988496
• NM_000823.4:c.169G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000823.4(GHRHR):​c.169G>A​(p.Ala57Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.065 in 1,578,878 control chromosomes in the GnomAD database, including 5,415 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A57V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (1800 hom., cov: 32)
  • Exomes 𝑓: 0.060 (3615 hom.)
• Consequence: GHRHR NM_000823.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0820
• Publications: 33 publications found

Genes affected

GHRHR (HGNC:4266): (growth hormone releasing hormone receptor) This gene encodes a receptor for growth hormone-releasing hormone. Binding of this hormone to the receptor leads to synthesis and release of growth hormone. Mutations in this gene have been associated with isolated growth hormone deficiency (IGHD), also known as Dwarfism of Sindh, a disorder characterized by short stature. [provided by RefSeq, Jun 2010]

GHRHR Gene-Disease associations (from GenCC):

• isolated growth hormone deficiency type IB

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet
• isolated growth hormone deficiency, type 4

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044107735).
• BP6: Variant 7-30969071-G-A is Benign according to our data. Variant chr7-30969071-G-A is described in ClinVar as Benign. ClinVar VariationId is 36273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHRHR	NM_000823.4	c.169G>A	p.Ala57Thr	missense_variant	Exon 3 of 13	ENST00000326139.7	NP_000814.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHRHR	ENST00000326139.7	c.169G>A	p.Ala57Thr	missense_variant	Exon 3 of 13	1	NM_000823.4	ENSP00000320180.2
GHRHR	ENST00000466427.1	n.*192G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17421 AN: 152030 Hom.: 1795 Cov.: 32

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0665

Gnomad ASJ AF: 0.0926

Gnomad EAS AF: 0.0637

Gnomad SAS AF: 0.0321

Gnomad FIN AF: 0.0160

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0551

Gnomad OTH AF: 0.101

GnomAD2 exomes AF: 0.0649 AC: 12633 AN: 194776 AF XY: 0.0599

Gnomad AFR exome AF: 0.289

Gnomad AMR exome AF: 0.0413

Gnomad ASJ exome AF: 0.0892

Gnomad EAS exome AF: 0.0695

Gnomad FIN exome AF: 0.0176

Gnomad NFE exome AF: 0.0557

Gnomad OTH exome AF: 0.0604

GnomAD4 exome AF: 0.0597 AC: 85206 AN: 1426728 Hom.: 3615 Cov.: 31 AF XY: 0.0583 AC XY: 41157 AN XY: 706398

African (AFR) AF: 0.284 AC: 9370 AN: 33008

American (AMR) AF: 0.0442 AC: 1715 AN: 38808

Ashkenazi Jewish (ASJ) AF: 0.0945 AC: 2399 AN: 25392

East Asian (EAS) AF: 0.0487 AC: 1874 AN: 38456

South Asian (SAS) AF: 0.0356 AC: 2906 AN: 81612

European-Finnish (FIN) AF: 0.0177 AC: 899 AN: 50910

Middle Eastern (MID) AF: 0.0972 AC: 556 AN: 5722

European-Non Finnish (NFE) AF: 0.0559 AC: 61176 AN: 1093704

Other (OTH) AF: 0.0729 AC: 4311 AN: 59116

GnomAD4 genome AF: 0.115 AC: 17444 AN: 152150 Hom.: 1800 Cov.: 32 AF XY: 0.110 AC XY: 8215 AN XY: 74384

African (AFR) AF: 0.274 AC: 11384 AN: 41472

American (AMR) AF: 0.0664 AC: 1016 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0926 AC: 321 AN: 3468

East Asian (EAS) AF: 0.0638 AC: 328 AN: 5140

South Asian (SAS) AF: 0.0322 AC: 155 AN: 4818

European-Finnish (FIN) AF: 0.0160 AC: 170 AN: 10620

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0551 AC: 3744 AN: 68008

Other (OTH) AF: 0.100 AC: 212 AN: 2114

Alfa AF: 0.0755 Hom.: 2147

Bravo AF: 0.128

TwinsUK AF: 0.0572 AC: 212

ALSPAC AF: 0.0586 AC: 226

ESP6500AA AF: 0.274 AC: 1204

ESP6500EA AF: 0.0573 AC: 492

ExAC AF: 0.0577 AC: 6947

Asia WGS AF: 0.0580 AC: 206 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28910730, 22449891, 10944436, 11502843) -

not specified Benign:1

Jun 01, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GHRHR-related disorder Benign:1

Oct 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Idiopathic growth hormone deficiency Benign:1

Aug 18, 2011

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Isolated growth hormone deficiency type IB Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.21
DANN	Benign	0.85
DEOGEN2	Benign	0.097	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0040	N
LIST_S2	Benign	0.011	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.36	N
PhyloP100		-0.082
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.031
Sift	Benign	0.12	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.016
MPC		0.087
ClinPred		0.0024	T
GERP RS		-7.8
PromoterAI		-0.0032	Neutral
Varity_R		0.11
gMVP		0.37
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4988496; hg19: chr7-31008686; COSMIC: COSV58196365; COSMIC: COSV58196365;