rs34223737

Variant names:

• chr5-42713407-G-A
• rs34223737
• NM_000163.5:c.785-22G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000163.5(GHR):​c.785-22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,059,712 control chromosomes in the GnomAD database, including 274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (135 hom., cov: 32)
  • Exomes 𝑓: 0.010 (139 hom.)
• Consequence: GHR NM_000163.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.271
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-42713407-G-A is Benign according to our data. Variant chr5-42713407-G-A is described in ClinVar as [Benign]. Clinvar id is 255407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5	c.785-22G>A		intron_variant	Intron 7 of 9	ENST00000230882.9	NP_000154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHR	ENST00000230882.9	c.785-22G>A		intron_variant	Intron 7 of 9	1	NM_000163.5	ENSP00000230882.4

Frequencies

GnomAD3 genomes AF: 0.0264 AC: 4016 AN: 152082 Hom.: 135 Cov.: 32

Gnomad AFR AF: 0.0770

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00747

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.00736

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00744

Gnomad OTH AF: 0.0186

GnomAD2 exomes AF: 0.0119 AC: 2965 AN: 248640 AF XY: 0.0111

Gnomad AFR exome AF: 0.0780

Gnomad AMR exome AF: 0.00342

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.00632

Gnomad NFE exome AF: 0.00809

Gnomad OTH exome AF: 0.0100

GnomAD4 exome AF: 0.0102 AC: 9238 AN: 907512 Hom.: 139 Cov.: 13 AF XY: 0.0101 AC XY: 4786 AN XY: 475290

African (AFR) AF: 0.0808 AC: 1864 AN: 23072

American (AMR) AF: 0.00423 AC: 186 AN: 44008

Ashkenazi Jewish (ASJ) AF: 0.00445 AC: 101 AN: 22714

East Asian (EAS) AF: 0.000216 AC: 8 AN: 36992

South Asian (SAS) AF: 0.0138 AC: 1037 AN: 75092

European-Finnish (FIN) AF: 0.00802 AC: 393 AN: 48976

Middle Eastern (MID) AF: 0.00942 AC: 44 AN: 4672

European-Non Finnish (NFE) AF: 0.00842 AC: 5132 AN: 609766

Other (OTH) AF: 0.0112 AC: 473 AN: 42220

GnomAD4 genome AF: 0.0264 AC: 4024 AN: 152200 Hom.: 135 Cov.: 32 AF XY: 0.0250 AC XY: 1859 AN XY: 74420

African (AFR) AF: 0.0770 AC: 3197 AN: 41520

American (AMR) AF: 0.00739 AC: 113 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0137 AC: 66 AN: 4828

European-Finnish (FIN) AF: 0.00736 AC: 78 AN: 10604

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.00744 AC: 506 AN: 67992

Other (OTH) AF: 0.0184 AC: 39 AN: 2116

Alfa AF: 0.0322 Hom.: 57

Bravo AF: 0.0281

Asia WGS AF: 0.0150 AC: 52 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.8
DANN	Benign	0.68
PhyloP100		0.27
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: rs34223737; hg19: chr5-42713509;