rs6183

chr5-42718990-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000163.5(GHR):c.1483C>A(p.Pro495Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000701 in 1,610,444 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P495P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (11 hom.)
• Consequence: GHR NM_000163.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.94

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008959115).
• BP6: Variant 5-42718990-C-A is Benign according to our data. Variant chr5-42718990-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 353685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-42718990-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00112 (170/152254) while in subpopulation EAS AF= 0.0288 (149/5176). AF 95% confidence interval is 0.025. There are 2 homozygotes in gnomad4. There are 99 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GHR	NM_000163.5	c.1483C>A	p.Pro495Thr	missense_variant	10/10	ENST00000230882.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHR	ENST00000230882.9	c.1483C>A	p.Pro495Thr	missense_variant	10/10	1	NM_000163.5	P1

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152136 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0289

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00229 AC: 572 AN: 249264 Hom.: 8 AF XY: 0.00209 AC XY: 282 AN XY: 134618

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0295

Gnomad SAS exome AF: 0.000467

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.000658 AC: 959 AN: 1458190 Hom.: 11 Cov.: 34 AF XY: 0.000625 AC XY: 453 AN XY: 724818

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000897

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0200

Gnomad4 SAS exome AF: 0.000571

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000721

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00112 AC: 170 AN: 152254 Hom.: 2 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74436

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0288

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000967 Hom.: 4

Bravo AF: 0.00122

ExAC AF: 0.00199 AC: 242

Asia WGS AF: 0.0160 AC: 57 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Laron-type isolated somatotropin defect Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.020
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;D;.;D;D;D;D;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.93	D
MetaRNN	Benign	0.0090	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	4.0	H;H;.;H;H;H;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.9	D;.;.;.;.;.;.;D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D
Polyphen		0.96	D;D;.;D;D;D;D;.
Vest4		0.53
MVP		0.91
MPC		0.32
ClinPred		0.19	T
GERP RS		5.8
Varity_R		0.82
gMVP		0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs6183; hg19: chr5-42719092;