rs2972408

Variant names:

• chr5-42463507-G-A
• rs2972408
• NM_000163.5:c.-12+39552G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000163.5(GHR):​c.-12+39552G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 152,004 control chromosomes in the GnomAD database, including 20,324 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (20324 hom., cov: 32)
• Consequence: GHR NM_000163.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.122
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5	c.-12+39552G>A		intron_variant	Intron 1 of 9	ENST00000230882.9	NP_000154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHR	ENST00000230882.9	c.-12+39552G>A		intron_variant	Intron 1 of 9	1	NM_000163.5	ENSP00000230882.4
GHR	ENST00000620156.4	c.10+38909G>A		intron_variant	Intron 1 of 9	5		ENSP00000483403.1
GHR	ENST00000615111.4	c.-297+38909G>A		intron_variant	Intron 1 of 10	5		ENSP00000478291.1
GHR	ENST00000513671.5	n.-12+38909G>A		intron_variant	Intron 1 of 5	4		ENSP00000426739.1

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76273 AN: 151886 Hom.: 20305 Cov.: 32

Gnomad AFR AF: 0.660

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.479

Gnomad ASJ AF: 0.474

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.460

Gnomad OTH AF: 0.512

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

GnomAD4 genome AF: 0.502 AC: 76336 AN: 152004 Hom.: 20324 Cov.: 32 AF XY: 0.497 AC XY: 36927 AN XY: 74298

African (AFR) AF: 0.660 AC: 27361 AN: 41454

American (AMR) AF: 0.478 AC: 7310 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.474 AC: 1643 AN: 3468

East Asian (EAS) AF: 0.115 AC: 596 AN: 5182

South Asian (SAS) AF: 0.357 AC: 1717 AN: 4812

European-Finnish (FIN) AF: 0.444 AC: 4674 AN: 10534

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.460 AC: 31242 AN: 67962

Other (OTH) AF: 0.507 AC: 1069 AN: 2108

Alfa AF: 0.521 Hom.: 3165

Bravo AF: 0.513

Asia WGS AF: 0.269 AC: 935 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.2
DANN	Benign	0.59
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2972408; hg19: chr5-42463609;