rs740336

chr7-30972062-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000409316.5(GHRHR):c.17C>T(p.Thr6Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,613,980 control chromosomes in the GnomAD database, including 1,264 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (322 hom., cov: 32)
  • Exomes 𝑓: 0.027 (942 hom.)
• Consequence: GHRHR ENST00000409316.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.82

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=0.0016007125).
• BP6: Variant 7-30972062-C-T is Benign according to our data. Variant chr7-30972062-C-T is described in ClinVar as [Benign]. Clinvar id is 36276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30972062-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GHRHR	NM_000823.4	c.564C>T	p.His188=	synonymous_variant	6/13	ENST00000326139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHRHR	ENST00000326139.7	c.564C>T	p.His188=	synonymous_variant	6/13	1	NM_000823.4	P1

Frequencies

GnomAD3 genomes AF: 0.0473 AC: 7193 AN: 152130 Hom.: 320 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0191

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00579

Gnomad SAS AF: 0.0767

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0221

Gnomad OTH AF: 0.0378

GnomAD3 exomes AF: 0.0312 AC: 7839 AN: 251420 Hom.: 258 AF XY: 0.0332 AC XY: 4518 AN XY: 135890

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.0127

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.00767

Gnomad SAS exome AF: 0.0791

Gnomad FIN exome AF: 0.00268

Gnomad NFE exome AF: 0.0225

Gnomad OTH exome AF: 0.0271

GnomAD4 exome AF: 0.0269 AC: 39322 AN: 1461732 Hom.: 942 Cov.: 32 AF XY: 0.0284 AC XY: 20652 AN XY: 727170

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.0136

Gnomad4 ASJ exome AF: 0.0174

Gnomad4 EAS exome AF: 0.00333

Gnomad4 SAS exome AF: 0.0789

Gnomad4 FIN exome AF: 0.00337

Gnomad4 NFE exome AF: 0.0224

Gnomad4 OTH exome AF: 0.0307

GnomAD4 genome AF: 0.0474 AC: 7213 AN: 152248 Hom.: 322 Cov.: 32 AF XY: 0.0468 AC XY: 3484 AN XY: 74444

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.0191

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00580

Gnomad4 SAS AF: 0.0774

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.0221

Gnomad4 OTH AF: 0.0397

Alfa AF: 0.0282 Hom.: 149

Bravo AF: 0.0507

TwinsUK AF: 0.0221 AC: 82

ALSPAC AF: 0.0239 AC: 92

ESP6500AA AF: 0.111 AC: 487

ESP6500EA AF: 0.0222 AC: 191

ExAC AF: 0.0343 AC: 4169

Asia WGS AF: 0.0450 AC: 156 AN: 3478

EpiCase AF: 0.0242

EpiControl AF: 0.0268

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

Idiopathic growth hormone deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing;curation

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

Jan 12, 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
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.33
Dann	Benign	0.24
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.020
Polyphen		0.23	B
Vest4		0.24
ClinPred		0.011	T
GERP RS		-6.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs740336; hg19: chr7-31011677;