20-37256490-C-A

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_021081.6(GHRH):​c.92G>T​(p.Arg31Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GHRH NM_021081.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.68

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHRH	NM_021081.6	c.92G>T	p.Arg31Leu	missense_variant	Exon 3 of 5	ENST00000373614.7	NP_066567.1
GHRH	NM_001184731.3	c.92G>T	p.Arg31Leu	missense_variant	Exon 3 of 5		NP_001171660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHRH	ENST00000373614.7	c.92G>T	p.Arg31Leu	missense_variant	Exon 3 of 5	1	NM_021081.6	ENSP00000362716.2
GHRH	ENST00000237527.8	c.92G>T	p.Arg31Leu	missense_variant	Exon 3 of 5	1		ENSP00000237527.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458308 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725404

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;D;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.2	M;M;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.96
MutPred		0.85		Loss of MoRF binding (P = 0.0176);Loss of MoRF binding (P = 0.0176);Loss of MoRF binding (P = 0.0176);
MVP		0.81
MPC		1.3
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.90
gMVP		0.88

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-35884893; COSMIC: COSV52902160;