chr7-30973975-T-C

Position:

• chr7-30973975-T-C

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.598-10T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0468 in 1,612,620 control chromosomes in the GnomAD database, including 4,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1704 hom., cov: 32)
  • Exomes 𝑓: 0.041 (2639 hom.)
• Consequence: GHRHR NM_000823.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00009625
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.29

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 (BayesDel_noAF=-0.91).
• BP6: Variant 7-30973975-T-C is Benign according to our data. Variant chr7-30973975-T-C is described in ClinVar as [Benign]. Clinvar id is 360031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GHRHR	NM_000823.4	c.598-10T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000326139.7	NP_000814.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GHRHR	ENST00000326139.7	c.598-10T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000823.4	ENSP00000320180	P1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15914 AN: 151694 Hom.: 1700 Cov.: 32

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.0565

Gnomad ASJ AF: 0.0817

Gnomad EAS AF: 0.0696

Gnomad SAS AF: 0.0915

Gnomad FIN AF: 0.0312

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0290

Gnomad OTH AF: 0.0872

GnomAD3 exomes AF: 0.0619 AC: 15392 AN: 248662 Hom.: 977 AF XY: 0.0600 AC XY: 8085 AN XY: 134656

Gnomad AFR exome AF: 0.279

Gnomad AMR exome AF: 0.0369

Gnomad ASJ exome AF: 0.0784

Gnomad EAS exome AF: 0.0742

Gnomad SAS exome AF: 0.0964

Gnomad FIN exome AF: 0.0325

Gnomad NFE exome AF: 0.0306

Gnomad OTH exome AF: 0.0604

GnomAD4 exome AF: 0.0408 AC: 59557 AN: 1460808 Hom.: 2639 Cov.: 33 AF XY: 0.0421 AC XY: 30607 AN XY: 726740

Gnomad4 AFR exome AF: 0.283

Gnomad4 AMR exome AF: 0.0393

Gnomad4 ASJ exome AF: 0.0756

Gnomad4 EAS exome AF: 0.0511

Gnomad4 SAS exome AF: 0.0941

Gnomad4 FIN exome AF: 0.0342

Gnomad4 NFE exome AF: 0.0271

Gnomad4 OTH exome AF: 0.0597

GnomAD4 genome AF: 0.105 AC: 15934 AN: 151812 Hom.: 1704 Cov.: 32 AF XY: 0.104 AC XY: 7740 AN XY: 74180

Gnomad4 AFR AF: 0.275

Gnomad4 AMR AF: 0.0564

Gnomad4 ASJ AF: 0.0817

Gnomad4 EAS AF: 0.0698

Gnomad4 SAS AF: 0.0910

Gnomad4 FIN AF: 0.0312

Gnomad4 NFE AF: 0.0290

Gnomad4 OTH AF: 0.0867

Alfa AF: 0.0815 Hom.: 391

Bravo AF: 0.116

Asia WGS AF: 0.100 AC: 350 AN: 3478

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

GHRHR-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 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). -

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
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.0
DANN	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000096
dbscSNV1_RF	Benign	0.0060
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: rs35609199; hg19: chr7-31013590;