rs4988504

Variant names:

• chr7-30976403-G-A
• rs4988504
• NM_000823.4:c.975-26G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-30976403-G-A
• chr7-30976403-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000823.4(GHRHR):​c.975-26G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,606,386 control chromosomes in the GnomAD database, including 9,664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.11 (913 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8751 hom.)
• Consequence: GHRHR NM_000823.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.447
• Publications: 9 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 -14 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-30976403-G-A is Benign according to our data. Variant chr7-30976403-G-A is described in ClinVar as Benign. ClinVar VariationId is 1226509.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHRHR	NM_000823.4	c.975-26G>A		intron_variant	Intron 10 of 12	ENST00000326139.7	NP_000814.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHRHR	ENST00000326139.7	c.975-26G>A		intron_variant	Intron 10 of 12	1	NM_000823.4	ENSP00000320180.2

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16056 AN: 152040 Hom.: 918 Cov.: 32

Gnomad AFR AF: 0.0892

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.0800

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.127

GnomAD2 exomes AF: 0.116 AC: 29055 AN: 251018 AF XY: 0.115

Gnomad AFR exome AF: 0.0861

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.164

Gnomad EAS exome AF: 0.182

Gnomad FIN exome AF: 0.0803

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.106 AC: 154043 AN: 1454228 Hom.: 8751 Cov.: 30 AF XY: 0.107 AC XY: 77555 AN XY: 723876

African (AFR) AF: 0.0897 AC: 2990 AN: 33348

American (AMR) AF: 0.134 AC: 5968 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 4279 AN: 26024

East Asian (EAS) AF: 0.207 AC: 8196 AN: 39632

South Asian (SAS) AF: 0.132 AC: 11362 AN: 85958

European-Finnish (FIN) AF: 0.0797 AC: 4208 AN: 52820

Middle Eastern (MID) AF: 0.182 AC: 1044 AN: 5752

European-Non Finnish (NFE) AF: 0.0987 AC: 109152 AN: 1105928

Other (OTH) AF: 0.114 AC: 6844 AN: 60080

GnomAD4 genome AF: 0.105 AC: 16042 AN: 152158 Hom.: 913 Cov.: 32 AF XY: 0.105 AC XY: 7775 AN XY: 74388

African (AFR) AF: 0.0892 AC: 3700 AN: 41502

American (AMR) AF: 0.125 AC: 1909 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 570 AN: 3468

East Asian (EAS) AF: 0.183 AC: 947 AN: 5166

South Asian (SAS) AF: 0.140 AC: 675 AN: 4812

European-Finnish (FIN) AF: 0.0800 AC: 849 AN: 10608

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6959 AN: 67990

Other (OTH) AF: 0.127 AC: 268 AN: 2114

Alfa AF: 0.101 Hom.: 648

Bravo AF: 0.111

Asia WGS AF: 0.149 AC: 518 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	12
DANN	Benign	0.77
PhyloP100		0.45
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs4988504; hg19: chr7-31016018; COSMIC: COSV58195924; COSMIC: COSV58195924;