dbSNP rs4988492: GHRH:p.Leu75Phe (chr20-37254295-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM1BP4_StrongBA1

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. 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
NM_021081.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.292

Publications

14 publications found

Variant links:

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]

GHRH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

In a modified_residue Leucine amide (size 0) in uniprot entity SLIB_HUMAN

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHRH	NM_021081.6 link	c.223C>T	p.Leu75Phe	missense_variant	Exon 4 of 5	ENST00000373614.7	NP_066567.1	P01286-1
GHRH	NM_001184731.3 link	c.223C>T	p.Leu75Phe	missense_variant	Exon 4 of 5		NP_001171660.1	P01286-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHRH	ENST00000373614.7 link	c.223C>T	p.Leu75Phe	missense_variant	Exon 4 of 5	1	NM_021081.6	ENSP00000362716.2		P01286-1
GHRH	ENST00000237527.8 link	c.223C>T	p.Leu75Phe	missense_variant	Exon 4 of 5	1		ENSP00000237527.4		P01286-2

Frequencies

GnomAD3 genomes

AF:

0.0375

AC:

5697

AN:

152080

Hom.:

171

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0177

AC XY:

12896

AN XY:

727172

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1372

2744

4117

5489

6861

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0376

AC:

5726

AN:

152198

Hom.:

173

Cov.:

AF XY:

0.0399

AC XY:

2968

AN XY:

74408

show subpopulations

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:

AN:

3470

East Asian (EAS)

AF:

0.0152

AC:

AN:

5186

South Asian (SAS)

AF:

0.00561

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0575

AC:

609

AN:

10584

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0176

AC:

1196

AN:

68012

Other (OTH)

AF:

0.0331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

262

523

785

1046

1308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0227

Hom.:

273

Bravo

AF:

0.0374

TwinsUK

AF:

0.0167

AC:

ALSPAC

AF:

0.0150

AC:

ESP6500AA

AF:

0.0726

AC:

320

ESP6500EA

AF:

0.0190

AC:

163

ExAC

AF:

0.0245

AC:

2973

Asia WGS

AF:

0.0230

AC:

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

BayesDel_noAF

Benign

-0.67

CADD

Benign

9.8

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

T;T;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.54

.;T;T

MetaRNN

Benign

0.0019

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;M;M

PhyloP100

0.29

PrimateAI

Benign

0.29

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

GERP RS

-0.96

Varity_R

0.046

gMVP

0.15

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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rs4988492

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over