rs2228078

chr7-30979237-T-Cchr7-30979237-T-G

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.1265T>C(p.Met422Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,613,800 control chromosomes in the GnomAD database, including 2,066 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (255 hom., cov: 33)
  • Exomes 𝑓: 0.023 (1811 hom.)
• Consequence: GHRHR NM_000823.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0660

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=0.00125435).
• BP6: Variant 7-30979237-T-C is Benign according to our data. Variant chr7-30979237-T-C is described in ClinVar as [Benign]. Clinvar id is 360037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30979237-T-C is described in Lovd as [Benign]. Variant chr7-30979237-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GHRHR	NM_000823.4	c.1265T>C	p.Met422Thr	missense_variant	13/13	ENST00000326139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHRHR	ENST00000326139.7	c.1265T>C	p.Met422Thr	missense_variant	13/13	1	NM_000823.4	P1

Frequencies

GnomAD3 genomes AF: 0.0289 AC: 4402 AN: 152236 Hom.: 252 Cov.: 33

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0370

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.0503 AC: 12634 AN: 251138 Hom.: 1351 AF XY: 0.0430 AC XY: 5843 AN XY: 135788

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.00353

Gnomad SAS exome AF: 0.0392

Gnomad FIN exome AF: 0.0112

Gnomad NFE exome AF: 0.0141

Gnomad OTH exome AF: 0.0391

GnomAD4 exome AF: 0.0232 AC: 33972 AN: 1461446 Hom.: 1811 Cov.: 31 AF XY: 0.0231 AC XY: 16767 AN XY: 727034

Gnomad4 AFR exome AF: 0.0117

Gnomad4 AMR exome AF: 0.243

Gnomad4 ASJ exome AF: 0.0190

Gnomad4 EAS exome AF: 0.00262

Gnomad4 SAS exome AF: 0.0397

Gnomad4 FIN exome AF: 0.0115

Gnomad4 NFE exome AF: 0.0149

Gnomad4 OTH exome AF: 0.0231

GnomAD4 genome AF: 0.0289 AC: 4407 AN: 152354 Hom.: 255 Cov.: 33 AF XY: 0.0310 AC XY: 2313 AN XY: 74502

Gnomad4 AFR AF: 0.0147

Gnomad4 AMR AF: 0.154

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.0364

Gnomad4 FIN AF: 0.0134

Gnomad4 NFE AF: 0.0142

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0155 Hom.: 73

Bravo AF: 0.0396

ESP6500AA AF: 0.0138 AC: 61

ESP6500EA AF: 0.0145 AC: 125

ExAC AF: 0.0410 AC: 4972

Asia WGS AF: 0.0220 AC: 75 AN: 3478

EpiCase AF: 0.0145

EpiControl AF: 0.0153

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 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 22449891) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 28, 2018

- -

Isolated growth hormone deficiency type IB Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	0.064
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	14
Dann	Benign	0.72
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.42	T;T
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	0.99	D;D;D;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.41	N;N
REVEL	Benign	0.077
Sift	Benign	0.20	T;T
Sift4G	Benign	0.074	T;T
Polyphen		0.026	B;B
Vest4		0.038
MPC		0.11
ClinPred		0.00082	T
GERP RS		-0.058
Varity_R		0.055
gMVP		0.51

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: rs2228078; hg19: chr7-31018852; COSMIC: COSV58198587; COSMIC: COSV58198587;