Genetic Variant GHSR:p.Leu149Leu (chr3-172447967-G-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_198407.2(GHSR):c.447C>G(p.Leu149Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0287 in 1,614,016 control chromosomes in the GnomAD database, including 918 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L149L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.036 ( 159 hom., cov: 32)

Exomes 𝑓: 0.028 ( 759 hom. )

Consequence

GHSR
NM_198407.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.207

Publications

11 publications found

Variant links:

Genes affected

GHSR (HGNC:4267): (growth hormone secretagogue receptor) This gene encodes a member of the G-protein coupled receptor family. The encoded protein may play a role in energy homeostasis and regulation of body weight. Two identified transcript variants are expressed in several tissues and are evolutionary conserved in fish and swine. One transcript, 1a, excises an intron and encodes the functional protein; this protein is the receptor for the Ghrelin ligand and defines a neuroendocrine pathway for growth hormone release. The second transcript (1b) retains the intron and does not function as a receptor for Ghrelin; however, it may function to attenuate activity of isoform 1a. Mutations in this gene are associated with autosomal idiopathic short stature.[provided by RefSeq, Apr 2010]

GHSR Gene-Disease associations (from GenCC):

short stature due to GHSR deficiency
Inheritance: AR, AD, SD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

GHSR links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 3-172447967-G-C is Benign according to our data. Variant chr3-172447967-G-C is described in ClinVar as Benign. ClinVar VariationId is 344200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.207 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0648 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198407.2. 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
	GHSR	NM_198407.2	MANE Select	c.447C>G	p.Leu149Leu	synonymous	Exon 1 of 2	NP_940799.1	Q92847-1
	GHSR	NM_004122.2		c.447C>G	p.Leu149Leu	synonymous	Exon 1 of 1	NP_004113.1	Q92847-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHSR	ENST00000241256.3	TSL:1 MANE Select	c.447C>G	p.Leu149Leu	synonymous	Exon 1 of 2	ENSP00000241256.2	Q92847-1
	GHSR	ENST00000427970.1	TSL:6	c.447C>G	p.Leu149Leu	synonymous	Exon 1 of 1	ENSP00000395344.1	Q92847-2

Frequencies

GnomAD3 genomes

AF:

0.0360

AC:

5473

AN:

152212

Hom.:

158

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0669

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0233

Gnomad ASJ

AF:

0.0285

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0406

Gnomad FIN

AF:

0.00837

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0274

Gnomad OTH

AF:

0.0388

GnomAD2 exomes

AF:

0.0277

AC:

6955

AN:

250954

AF XY:

0.0286

show subpopulations

Gnomad AFR exome

AF:

0.0680

Gnomad AMR exome

AF:

0.0138

Gnomad ASJ exome

AF:

0.0322

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.00861

Gnomad NFE exome

AF:

0.0284

Gnomad OTH exome

AF:

0.0328

GnomAD4 exome

AF:

0.0279

AC:

40838

AN:

1461686

Hom.:

759

Cov.:

AF XY:

0.0284

AC XY:

20659

AN XY:

727086

show subpopulations

African (AFR)

AF:

0.0715

AC:

2393

AN:

33478

American (AMR)

AF:

0.0154

AC:

688

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0326

AC:

852

AN:

26132

East Asian (EAS)

AF:

0.000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.0485

AC:

4186

AN:

86252

European-Finnish (FIN)

AF:

0.00908

AC:

485

AN:

53412

Middle Eastern (MID)

AF:

0.0668

AC:

385

AN:

5766

European-Non Finnish (NFE)

AF:

0.0269

AC:

29913

AN:

1111848

Other (OTH)

AF:

0.0319

AC:

1926

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

2633

5266

7898

10531

13164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1178

2356

3534

4712

5890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0360

AC:

5477

AN:

152330

Hom.:

159

Cov.:

AF XY:

0.0353

AC XY:

2630

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0668

AC:

2778

AN:

41570

American (AMR)

AF:

0.0232

AC:

355

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0285

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0406

AC:

196

AN:

4828

European-Finnish (FIN)

AF:

0.00837

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0274

AC:

1863

AN:

68028

Other (OTH)

AF:

0.0384

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

261

522

784

1045

1306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0228

Hom.:

Bravo

AF:

0.0379

EpiCase

AF:

0.0276

EpiControl

AF:

0.0285

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Short stature due to growth hormone secretagogue receptor deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.68

PhyloP100

0.21

PromoterAI

-0.0070

Neutral

(source)

Mutation Taster

=97/3

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over