rs1381777610

Variant names:

• chr7-30964084-TG-T
• rs1381777610
• NM_000823.4:c.22delG

Your query was ambiguous. Multiple possible variants found:

• chr7-30964084-TG-T
• chr7-30964084-TG-TGG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000823.4(GHRHR):​c.22delG​(p.Ala8ProfsTer7) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000715 in 1,398,280 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: GHRHR NM_000823.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.74
• Publications: 0 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: Orphanet, Laboratory for Molecular Medicine
• isolated growth hormone deficiency, type 4

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 30 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-30964084-TG-T is Pathogenic according to our data. Variant chr7-30964084-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3616306.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000823.4. 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
	GHRHR	NM_000823.4	MANE Select	c.22delG	p.Ala8ProfsTer7	frameshift	Exon 1 of 13	NP_000814.2	A0A090N8Y6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHRHR	ENST00000326139.7	TSL:1 MANE Select	c.22delG	p.Ala8ProfsTer7	frameshift	Exon 1 of 13	ENSP00000320180.2	Q02643
	GHRHR	ENST00000466427.1	TSL:5	n.285-4744delG		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398280 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 689680

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078936

Other (OTH) AF: 0.00 AC: 0 AN: 57974

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7

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: rs1381777610; hg19: chr7-31003699; COSMIC: COSV105219159;