20-37256820-G-A

Variant names:

• chr20-37256820-G-A
• rs368337505
• NM_021081.6:c.70C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021081.6(GHRH):​c.70C>T​(p.Pro24Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P24T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GHRH NM_021081.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.784
• Publications: 0 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.028473377).

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.70C>T	p.Pro24Ser	missense	Exon 2 of 5	NP_066567.1	P01286-1
	GHRH	NM_001184731.3		c.70C>T	p.Pro24Ser	missense	Exon 2 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.70C>T	p.Pro24Ser	missense	Exon 2 of 5	ENSP00000362716.2	P01286-1
	GHRH	ENST00000237527.8	TSL:1	c.70C>T	p.Pro24Ser	missense	Exon 2 of 5	ENSP00000237527.4	P01286-2
	GHRH	ENST00000964612.1		c.70C>T	p.Pro24Ser	missense	Exon 2 of 5	ENSP00000634671.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460292 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726406

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 85920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111316

Other (OTH) AF: 0.00 AC: 0 AN: 60302

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.4
DANN	Benign	0.28
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.77	N
PhyloP100		0.78
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.51	N
REVEL	Benign	0.017
Sift	Benign	0.77	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.074
MutPred		0.24		Loss of catalytic residue at P23 (P = 0.064)
MVP		0.10
MPC		0.37
ClinPred		0.053	T
GERP RS		1.5
Varity_R		0.015
gMVP		0.38
Mutation Taster		=95/5	polymorphism

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: rs368337505; hg19: chr20-35885223;