Genetic Variant GHR:c.-12+243_-12+264dupGTGTGTGTGTGTGTGTGTGTGT (chr5-42424171-A-AGTGTGTGTGTGTGTGTGTGTGT) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_000163.5(GHR):c.-12+243_-12+264dupGTGTGTGTGTGTGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00032 ( 1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000318 (32/100580) while in subpopulation AFR AF = 0.000867 (21/24226). AF 95% confidence interval is 0.00058. There are 1 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5 link	c.-12+243_-12+264dupGTGTGTGTGTGTGTGTGTGTGT		intron_variant	Intron 1 of 9	ENST00000230882.9	NP_000154.1	P10912-1
GHR	NM_001242460.2 link	c.-12+243_-12+264dupGTGTGTGTGTGTGTGTGTGTGT		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+217insGTGTGTGTGTGTGTGTGTGTGT		intron_variant	Intron 1 of 9	1	NM_000163.5	ENSP00000230882.4		P10912-1

Frequencies

GnomAD3 genomes

AF:

0.000318

AC:

AN:

100512

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000870

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000309

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000202

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000179

Gnomad OTH

AF:

0.00

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

GnomAD4 genome

AF:

0.000318

AC:

AN:

100580

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

AN XY:

46752

show subpopulations

African (AFR)

AF:

0.000867

AC:

AN:

24226

American (AMR)

AF:

0.00

AC:

AN:

10354

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2658

East Asian (EAS)

AF:

0.000311

AC:

AN:

3218

South Asian (SAS)

AF:

0.00

AC:

AN:

2520

European-Finnish (FIN)

AF:

0.000202

AC:

AN:

4950

Middle Eastern (MID)

AF:

0.00

AC:

AN:

190

European-Non Finnish (NFE)

AF:

0.000179

AC:

AN:

50396

Other (OTH)

AF:

0.00

AC:

AN:

1370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.2

Splicing

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

Publications

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chr5-42424171-A-AGTGTGTGTGTGTGTGTGTGTGT

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