rs267606843

Variant names:

• chr3-172448408-C-T
• rs267606843
• NM_198407.2:c.6G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-172448408-C-T
• chr3-172448408-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_198407.2(GHSR):​c.6G>A​(p.Trp2*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GHSR NM_198407.2 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.660
• Publications: 3 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: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-172448408-C-T is Pathogenic according to our data. Variant chr3-172448408-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 7633.Status of the report is no_assertion_criteria_provided, 0 stars.

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.6G>A	p.Trp2*	stop_gained	Exon 1 of 2	NP_940799.1	Q92847-1
	GHSR	NM_004122.2		c.6G>A	p.Trp2*	stop_gained	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.6G>A	p.Trp2*	stop_gained	Exon 1 of 2	ENSP00000241256.2	Q92847-1
	GHSR	ENST00000427970.1	TSL:6	c.6G>A	p.Trp2*	stop_gained	Exon 1 of 1	ENSP00000395344.1	Q92847-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1439236 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 715854

African (AFR) AF: 0.00 AC: 0 AN: 33194

American (AMR) AF: 0.00 AC: 0 AN: 43810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25962

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39074

South Asian (SAS) AF: 0.00 AC: 0 AN: 84892

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5388

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108668

Other (OTH) AF: 0.00 AC: 0 AN: 59906

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Short stature due to growth hormone secretagogue receptor deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.76	D
PhyloP100		0.66
Vest4		0.51
GERP RS		4.5
PromoterAI		0.0092	Neutral
Mutation Taster		=8/192	disease causing (ClinVar)

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: rs267606843; hg19: chr3-172166198;