chr20-37256490-C-T

Variant names:

• chr20-37256490-C-T
• rs770654030
• NM_021081.6:c.92G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_021081.6(GHRH):​c.92G>A​(p.Arg31Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000686 in 1,458,308 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: GHRH NM_021081.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.68
• Publications: 2 publications found

Genes affected

GHRH (HGNC:4265): (growth hormone releasing hormone) This gene encodes a member of the glucagon family of proteins. The encoded preproprotein is produced in the hypothalamus and cleaved to generate the mature factor, known as somatoliberin, which acts to stimulate growth hormone release from the pituitary gland. Variant receptors for somatoliberin have been found in several types of tumors, and antagonists of these receptors can inhibit the growth of the tumors. Defects in this gene are a cause of dwarfism, while hypersecretion of the encoded protein is a cause of gigantism. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021081.6. 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
	GHRH	NM_021081.6	MANE Select	c.92G>A	p.Arg31Gln	missense	Exon 3 of 5	NP_066567.1	P01286-1
	GHRH	NM_001184731.3		c.92G>A	p.Arg31Gln	missense	Exon 3 of 5	NP_001171660.1	P01286-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHRH	ENST00000373614.7	TSL:1 MANE Select	c.92G>A	p.Arg31Gln	missense	Exon 3 of 5	ENSP00000362716.2	P01286-1
	GHRH	ENST00000237527.8	TSL:1	c.92G>A	p.Arg31Gln	missense	Exon 3 of 5	ENSP00000237527.4	P01286-2
	GHRH	ENST00000964612.1		c.92G>A	p.Arg31Gln	missense	Exon 3 of 5	ENSP00000634671.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249416 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1458308 Hom.: 0 Cov.: 30 AF XY: 0.00000689 AC XY: 5 AN XY: 725404

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.0000224 AC: 1 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52786

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1109686

Other (OTH) AF: 0.0000166 AC: 1 AN: 60270

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.84		Loss of MoRF binding (P = 0.0386)
MVP		0.77
MPC		1.2
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.88
gMVP		0.83
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs770654030; hg19: chr20-35884893; COSMIC: COSV52902113;