rs4988492

Variant names:

• chr20-37254295-G-A
• rs4988492
• NM_021081.6:c.223C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000373614.7(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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.038 (173 hom., cov: 32)
  • Exomes 𝑓: 0.018 (409 hom.)
• Consequence: GHRH ENST00000373614.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.292
• Publications: 14 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018500984).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0755 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000373614.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHRH	NM_021081.6	MANE Select	c.223C>T	p.Leu75Phe	missense	Exon 4 of 5	NP_066567.1
	GHRH	NM_001184731.3		c.223C>T	p.Leu75Phe	missense	Exon 4 of 5	NP_001171660.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHRH	ENST00000373614.7	TSL:1 MANE Select	c.223C>T	p.Leu75Phe	missense	Exon 4 of 5	ENSP00000362716.2
	GHRH	ENST00000237527.8	TSL:1	c.223C>T	p.Leu75Phe	missense	Exon 4 of 5	ENSP00000237527.4

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

GnomAD2 exomes AF: 0.0245 AC: 6159 AN: 251486 AF XY: 0.0218

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 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

African (AFR) AF: 0.0806 AC: 2698 AN: 33476

American (AMR) AF: 0.0336 AC: 1504 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00325 AC: 85 AN: 26136

East Asian (EAS) AF: 0.0237 AC: 941 AN: 39700

South Asian (SAS) AF: 0.00361 AC: 311 AN: 86256

European-Finnish (FIN) AF: 0.0501 AC: 2678 AN: 53420

Middle Eastern (MID) AF: 0.0446 AC: 257 AN: 5768

European-Non Finnish (NFE) AF: 0.0155 AC: 17283 AN: 1111876

Other (OTH) AF: 0.0191 AC: 1152 AN: 60388

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

African (AFR) AF: 0.0778 AC: 3228 AN: 41512

American (AMR) AF: 0.0327 AC: 501 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.0152 AC: 79 AN: 5186

South Asian (SAS) AF: 0.00561 AC: 27 AN: 4816

European-Finnish (FIN) AF: 0.0575 AC: 609 AN: 10584

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0176 AC: 1196 AN: 68012

Other (OTH) AF: 0.0331 AC: 70 AN: 2112

Alfa AF: 0.0227 Hom.: 273

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 v4.9

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
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.29
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.018
Sift	Benign	0.30	T
Sift4G	Benign	0.30	T
Polyphen		0.14	B
Vest4		0.030
MPC		0.40
ClinPred		0.0034	T
GERP RS		-0.96
Varity_R		0.046
gMVP		0.15
Mutation Taster		=98/2	polymorphism (auto)

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