rs4988496

chr7-30969071-G-A

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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 Likely benign.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
GHRHR	NM_000823.4	c.169G>A	p.Ala57Thr	missense_variant	3/13	ENST00000326139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHRHR	ENST00000326139.7	c.169G>A	p.Ala57Thr	missense_variant	3/13	1	NM_000823.4	P1

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

GnomAD3 exomes AF: 0.0649 AC: 12633 AN: 194776 Hom.: 781 AF XY: 0.0599 AC XY: 6220 AN XY: 103760

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 SAS exome AF: 0.0341

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

Gnomad4 AFR exome AF: 0.284

Gnomad4 AMR exome AF: 0.0442

Gnomad4 ASJ exome AF: 0.0945

Gnomad4 EAS exome AF: 0.0487

Gnomad4 SAS exome AF: 0.0356

Gnomad4 FIN exome AF: 0.0177

Gnomad4 NFE exome AF: 0.0559

Gnomad4 OTH exome AF: 0.0729

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

Gnomad4 AFR AF: 0.274

Gnomad4 AMR AF: 0.0664

Gnomad4 ASJ AF: 0.0926

Gnomad4 EAS AF: 0.0638

Gnomad4 SAS AF: 0.0322

Gnomad4 FIN AF: 0.0160

Gnomad4 NFE AF: 0.0551

Gnomad4 OTH AF: 0.100

Alfa AF: 0.0673 Hom.: 1095

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 28910730, 22449891, 10944436, 11502843) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 01, 2015

- -

GHRHR-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

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

Benign, criteria provided, single submitter

clinical testing

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

Aug 18, 2011

- -

Isolated growth hormone deficiency type IB Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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
MutationTaster	Benign	1.0	P
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
Varity_R		0.11
gMVP		0.37

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

Other links and lift over

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