rs4988509

Variant names:

• chr3-172447883-G-T
• rs4988509
• NM_198407.2:c.531C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-172447883-G-T
• chr3-172447883-G-A
• chr3-172447883-G-C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_198407.2(GHSR):​c.531C>A​(p.Pro177Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,613,452 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0044 (25 hom.)
• Consequence: GHSR NM_198407.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: 2.38
• Publications: 4 publications found

Genes affected

GHSR (HGNC:4267): (growth hormone secretagogue receptor) This gene encodes a member of the G-protein coupled receptor family. The encoded protein may play a role in energy homeostasis and regulation of body weight. Two identified transcript variants are expressed in several tissues and are evolutionary conserved in fish and swine. One transcript, 1a, excises an intron and encodes the functional protein; this protein is the receptor for the Ghrelin ligand and defines a neuroendocrine pathway for growth hormone release. The second transcript (1b) retains the intron and does not function as a receptor for Ghrelin; however, it may function to attenuate activity of isoform 1a. Mutations in this gene are associated with autosomal idiopathic short stature.[provided by RefSeq, Apr 2010]

GHSR Gene-Disease associations (from GenCC):

• short stature due to GHSR deficiency

  Inheritance: AR, AD, SD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 3-172447883-G-T is Benign according to our data. Variant chr3-172447883-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 698005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.38 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198407.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHSR	NM_198407.2	MANE Select	c.531C>A	p.Pro177Pro	synonymous	Exon 1 of 2	NP_940799.1	Q92847-1
	GHSR	NM_004122.2		c.531C>A	p.Pro177Pro	synonymous	Exon 1 of 1	NP_004113.1	Q92847-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHSR	ENST00000241256.3	TSL:1 MANE Select	c.531C>A	p.Pro177Pro	synonymous	Exon 1 of 2	ENSP00000241256.2	Q92847-1
	GHSR	ENST00000427970.1	TSL:6	c.531C>A	p.Pro177Pro	synonymous	Exon 1 of 1	ENSP00000395344.1	Q92847-2

Frequencies

GnomAD3 genomes AF: 0.00313 AC: 477 AN: 152218 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00535

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00343 AC: 858 AN: 250346 AF XY: 0.00343

Gnomad AFR exome AF: 0.000992

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00501

Gnomad NFE exome AF: 0.00596

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00438 AC: 6395 AN: 1461116 Hom.: 25 Cov.: 30 AF XY: 0.00425 AC XY: 3090 AN XY: 726720

African (AFR) AF: 0.000598 AC: 20 AN: 33466

American (AMR) AF: 0.000626 AC: 28 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000649 AC: 56 AN: 86244

European-Finnish (FIN) AF: 0.00508 AC: 271 AN: 53298

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.00519 AC: 5770 AN: 1111458

Other (OTH) AF: 0.00379 AC: 229 AN: 60354

GnomAD4 genome AF: 0.00313 AC: 477 AN: 152336 Hom.: 2 Cov.: 31 AF XY: 0.00298 AC XY: 222 AN XY: 74510

African (AFR) AF: 0.000721 AC: 30 AN: 41582

American (AMR) AF: 0.00229 AC: 35 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00386 AC: 41 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00535 AC: 364 AN: 68034

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00444 Hom.: 0

Bravo AF: 0.00260

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	-	1	Short stature due to growth hormone secretagogue receptor deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.85
PhyloP100		2.4
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs4988509; hg19: chr3-172165673;