Genetic Variant GHR:c.-12+255_-12+264dupGTGTGTGTGT (chr5-42424171-A-AGTGTGTGTGT) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_000163.5(GHR):c.-12+255_-12+264dupGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.035 ( 191 hom., cov: 0)

Consequence

GHR
NM_000163.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.21

Publications

0 publications found

Variant links:

Genes affected

GHR (HGNC:4263): (growth hormone receptor) This gene encodes a member of the type I cytokine receptor family, which is a transmembrane receptor for growth hormone. Binding of growth hormone to the receptor leads to receptor dimerization and the activation of an intra- and intercellular signal transduction pathway leading to growth. Mutations in this gene have been associated with Laron syndrome, also known as the growth hormone insensitivity syndrome (GHIS), a disorder characterized by short stature. In humans and rabbits, but not rodents, growth hormone binding protein (GHBP) is generated by proteolytic cleavage of the extracellular ligand-binding domain from the mature growth hormone receptor protein. Multiple alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Jun 2011]

GHR Gene-Disease associations (from GenCC):

Laron syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
short stature due to partial GHR deficiency
Inheritance: Unknown, AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

GHR links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0348 (3498/100522) while in subpopulation NFE AF = 0.0393 (1981/50376). AF 95% confidence interval is 0.0379. There are 191 homozygotes in GnomAd4. There are 1622 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 191 AR,Unknown,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5 link	c.-12+255_-12+264dupGTGTGTGTGT		intron_variant	Intron 1 of 9	ENST00000230882.9	NP_000154.1	P10912-1
GHR	NM_001242460.2 link	c.-12+255_-12+264dupGTGTGTGTGT		intron_variant	Intron 1 of 8		NP_001229389.1	P10912-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHR	ENST00000230882.9 link	c.-12+216_-12+217insGTGTGTGTGT		intron_variant	Intron 1 of 9	1	NM_000163.5	ENSP00000230882.4		P10912-1

Frequencies

GnomAD3 genomes

AF:

0.0349

AC:

3504

AN:

100454

Hom.:

191

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0254

Gnomad AMI

AF:

0.0716

Gnomad AMR

AF:

0.0255

Gnomad ASJ

AF:

0.0373

Gnomad EAS

AF:

0.0388

Gnomad SAS

AF:

0.0233

Gnomad FIN

AF:

0.0516

Gnomad MID

AF:

0.0250

Gnomad NFE

AF:

0.0393

Gnomad OTH

AF:

0.0388

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0348

AC:

3498

AN:

100522

Hom.:

191

Cov.:

AF XY:

0.0347

AC XY:

1622

AN XY:

46720

show subpopulations

African (AFR)

AF:

0.0253

AC:

612

AN:

24216

American (AMR)

AF:

0.0252

AC:

261

AN:

10350

Ashkenazi Jewish (ASJ)

AF:

0.0373

AC:

AN:

2656

East Asian (EAS)

AF:

0.0386

AC:

124

AN:

3210

South Asian (SAS)

AF:

0.0234

AC:

AN:

2518

European-Finnish (FIN)

AF:

0.0516

AC:

255

AN:

4944

Middle Eastern (MID)

AF:

0.0263

AC:

AN:

190

European-Non Finnish (NFE)

AF:

0.0393

AC:

1981

AN:

50376

Other (OTH)

AF:

0.0381

AC:

AN:

1364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

134

268

403

537

671

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

144

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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5-42424171-AGTGTGTGTGTGTGTGTGTGTGTGTGTGT-AGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over