NM_000163.5:c.-12+646A>T

Variant names:

• chr5-42424601-A-T
• rs116297749
• NM_000163.5:c.-12+646A>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000163.5(GHR):​c.-12+646A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00073 in 1,534,386 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (3 hom.)
• Consequence: GHR NM_000163.5 intron
• Scores: Splicing: ADA: 0.9199
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.306
• Publications: 1 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-42424601-A-T is Benign according to our data. Variant chr5-42424601-A-T is described in ClinVar as [Benign]. Clinvar id is 3035850.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00393 (598/152272) while in subpopulation AFR AF = 0.014 (580/41576). AF 95% confidence interval is 0.013. There are 4 homozygotes in GnomAd4. There are 261 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,Unknown,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5	c.-12+646A>T		intron_variant	Intron 1 of 9	ENST00000230882.9	NP_000154.1
GHR	NM_001242399.2	c.10+3A>T		splice_region_variant, intron_variant	Intron 1 of 9		NP_001229328.1
GHR	NM_001242400.2	c.-297+3A>T		splice_region_variant, intron_variant	Intron 1 of 10		NP_001229329.1
GHR	NM_001242460.2	c.-12+646A>T		intron_variant	Intron 1 of 8		NP_001229389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHR	ENST00000230882.9	c.-12+646A>T		intron_variant	Intron 1 of 9	1	NM_000163.5	ENSP00000230882.4
GHR	ENST00000620156.4	c.10+3A>T		splice_region_variant, intron_variant	Intron 1 of 9	5		ENSP00000483403.1
GHR	ENST00000615111.4	c.-297+3A>T		splice_region_variant, intron_variant	Intron 1 of 10	5		ENSP00000478291.1
GHR	ENST00000513671.5	n.-12+3A>T		splice_region_variant, intron_variant	Intron 1 of 5	4		ENSP00000426739.1

Frequencies

GnomAD3 genomes AF: 0.00391 AC: 595 AN: 152154 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000749 AC: 96 AN: 128114 AF XY: 0.000585

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.000328

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000250

GnomAD4 exome AF: 0.000378 AC: 522 AN: 1382114 Hom.: 3 Cov.: 29 AF XY: 0.000315 AC XY: 215 AN XY: 682058

African (AFR) AF: 0.0148 AC: 466 AN: 31546

American (AMR) AF: 0.000364 AC: 13 AN: 35692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35728

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33480

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5684

European-Non Finnish (NFE) AF: 0.00000464 AC: 5 AN: 1077772

Other (OTH) AF: 0.000588 AC: 34 AN: 57836

GnomAD4 genome AF: 0.00393 AC: 598 AN: 152272 Hom.: 4 Cov.: 32 AF XY: 0.00351 AC XY: 261 AN XY: 74458

African (AFR) AF: 0.0140 AC: 580 AN: 41576

American (AMR) AF: 0.000915 AC: 14 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00201 Hom.: 0

Bravo AF: 0.00459

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

GHR-related disorder Benign:1

Oct 31, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.58
PhyloP100		0.31
PromoterAI		-0.077	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Benign	0.52
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.42		Position offset: -41

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

Other links and lift over

dbSNP: rs116297749; hg19: chr5-42424703;