rs35609199

Variant names:

• chr7-30973975-T-C
• rs35609199
• NM_000823.4:c.598-10T>C

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.598-10T>C variant causes a 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 intron
• Scores: Splicing: ADA: 0.00009625
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.29
• Publications: 7 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 (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 VariationId 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 rank	MANE	Protein	UniProt
GHRHR	NM_000823.4	c.598-10T>C		intron_variant	Intron 6 of 12	ENST00000326139.7	NP_000814.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHRHR	ENST00000326139.7	c.598-10T>C		intron_variant	Intron 6 of 12	1	NM_000823.4	ENSP00000320180.2

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

GnomAD2 exomes AF: 0.0619 AC: 15392 AN: 248662 AF XY: 0.0600

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 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

African (AFR) AF: 0.283 AC: 9461 AN: 33476

American (AMR) AF: 0.0393 AC: 1757 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0756 AC: 1977 AN: 26134

East Asian (EAS) AF: 0.0511 AC: 2030 AN: 39694

South Asian (SAS) AF: 0.0941 AC: 8116 AN: 86252

European-Finnish (FIN) AF: 0.0342 AC: 1795 AN: 52554

Middle Eastern (MID) AF: 0.113 AC: 651 AN: 5766

European-Non Finnish (NFE) AF: 0.0271 AC: 30162 AN: 1111826

Other (OTH) AF: 0.0597 AC: 3608 AN: 60386

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

African (AFR) AF: 0.275 AC: 11369 AN: 41320

American (AMR) AF: 0.0564 AC: 862 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0817 AC: 283 AN: 3466

East Asian (EAS) AF: 0.0698 AC: 359 AN: 5144

South Asian (SAS) AF: 0.0910 AC: 433 AN: 4760

European-Finnish (FIN) AF: 0.0312 AC: 331 AN: 10596

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0290 AC: 1971 AN: 67936

Other (OTH) AF: 0.0867 AC: 183 AN: 2110

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

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GHRHR-related disorder Benign:1

Nov 06, 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). -

Isolated growth hormone deficiency type IB Benign:1

Jan 13, 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
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.0
DANN	Benign	0.40
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35609199; hg19: chr7-31013590;