rs4988492

Positions:

• chr20-37254295-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_021081.6(GHRH):​c.223C>T​(p.Leu75Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,613,942 control chromosomes in the GnomAD database, including 582 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.038 (173 hom., cov: 32)
  • Exomes 𝑓: 0.018 (409 hom.)
• Consequence: GHRH NM_021081.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.292

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018500984).
• BP6: Variant 20-37254295-G-A is Benign according to our data. Variant chr20-37254295-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GHRH	NM_021081.6	c.223C>T	p.Leu75Phe	missense_variant	4/5	ENST00000373614.7	NP_066567.1
GHRH	NM_001184731.3	c.223C>T	p.Leu75Phe	missense_variant	4/5		NP_001171660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GHRH	ENST00000373614.7	c.223C>T	p.Leu75Phe	missense_variant	4/5	1	NM_021081.6	ENSP00000362716	A1
GHRH	ENST00000237527.8	c.223C>T	p.Leu75Phe	missense_variant	4/5	1		ENSP00000237527	P4

Frequencies

GnomAD3 genomes AF: 0.0375 AC: 5697 AN: 152080 Hom.: 171 Cov.: 32

Gnomad AFR AF: 0.0772

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0329

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.0150

Gnomad SAS AF: 0.00581

Gnomad FIN AF: 0.0575

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0176

Gnomad OTH AF: 0.0330

GnomAD3 exomes AF: 0.0245 AC: 6159 AN: 251486 Hom.: 150 AF XY: 0.0218 AC XY: 2965 AN XY: 135920

Gnomad AFR exome AF: 0.0823

Gnomad AMR exome AF: 0.0338

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.0138

Gnomad SAS exome AF: 0.00304

Gnomad FIN exome AF: 0.0529

Gnomad NFE exome AF: 0.0173

Gnomad OTH exome AF: 0.0262

GnomAD4 exome AF: 0.0184 AC: 26909 AN: 1461744 Hom.: 409 Cov.: 31 AF XY: 0.0177 AC XY: 12896 AN XY: 727172

Gnomad4 AFR exome AF: 0.0806

Gnomad4 AMR exome AF: 0.0336

Gnomad4 ASJ exome AF: 0.00325

Gnomad4 EAS exome AF: 0.0237

Gnomad4 SAS exome AF: 0.00361

Gnomad4 FIN exome AF: 0.0501

Gnomad4 NFE exome AF: 0.0155

Gnomad4 OTH exome AF: 0.0191

GnomAD4 genome AF: 0.0376 AC: 5726 AN: 152198 Hom.: 173 Cov.: 32 AF XY: 0.0399 AC XY: 2968 AN XY: 74408

Gnomad4 AFR AF: 0.0778

Gnomad4 AMR AF: 0.0327

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.0152

Gnomad4 SAS AF: 0.00561

Gnomad4 FIN AF: 0.0575

Gnomad4 NFE AF: 0.0176

Gnomad4 OTH AF: 0.0331

Alfa AF: 0.0205 Hom.: 99

Bravo AF: 0.0374

TwinsUK AF: 0.0167 AC: 62

ALSPAC AF: 0.0150 AC: 58

ESP6500AA AF: 0.0726 AC: 320

ESP6500EA AF: 0.0190 AC: 163

ExAC AF: 0.0245 AC: 2973

Asia WGS AF: 0.0230 AC: 82 AN: 3478

EpiCase AF: 0.0170

EpiControl AF: 0.0180

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	9.8
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T;T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.54	.;T;T
MetaRNN	Benign	0.0019	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M;M
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.21	N;N;N
REVEL	Benign	0.018
Sift	Benign	0.30	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.14	B;B;B
Vest4		0.030
MPC		0.40
ClinPred		0.0034	T
GERP RS		-0.96
Varity_R		0.046
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs4988492; hg19: chr20-35882698; COSMIC: COSV52902362;