chr20-37256476-T-A

Variant names:

• chr20-37256476-T-A
• rs28932185
• NM_021081.6:c.106A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021081.6(GHRH):​c.106A>T​(p.Ile36Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: GHRH NM_021081.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.14

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHRH	NM_021081.6	c.106A>T	p.Ile36Phe	missense_variant	Exon 3 of 5	ENST00000373614.7	NP_066567.1
GHRH	NM_001184731.3	c.106A>T	p.Ile36Phe	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.106A>T	p.Ile36Phe	missense_variant	Exon 3 of 5	1	NM_021081.6	ENSP00000362716.2
GHRH	ENST00000237527.8	c.106A>T	p.Ile36Phe	missense_variant	Exon 3 of 5	1		ENSP00000237527.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;D;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Pathogenic	3.0	M;M;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.92
MutPred		0.65		Loss of MoRF binding (P = 0.0992);Loss of MoRF binding (P = 0.0992);Loss of MoRF binding (P = 0.0992);
MVP		0.61
MPC		1.4
ClinPred		0.96	D
GERP RS		3.9
Varity_R		0.88
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28932185; hg19: chr20-35884879;