rs149475648

chr5-42688855-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000163.5(GHR):c.137-35G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00592 in 1,607,914 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0042 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (38 hom.)
• Consequence: GHR NM_000163.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.204

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 5-42688855-G-C is Benign according to our data. Variant chr5-42688855-G-C is described in ClinVar as [Benign]. Clinvar id is 255403.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00418 (637/152290) while in subpopulation NFE AF= 0.00682 (464/68018). AF 95% confidence interval is 0.00631. There are 2 homozygotes in gnomad4. There are 292 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.137-35G>C		intron_variant		ENST00000230882.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHR	ENST00000230882.9	c.137-35G>C		intron_variant		1	NM_000163.5	P1

Frequencies

GnomAD3 genomes AF: 0.00419 AC: 637 AN: 152172 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00682

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00380 AC: 953 AN: 251104 Hom.: 8 AF XY: 0.00377 AC XY: 512 AN XY: 135686

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00635

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00610 AC: 8876 AN: 1455624 Hom.: 38 Cov.: 30 AF XY: 0.00593 AC XY: 4294 AN XY: 724540

Gnomad4 AFR exome AF: 0.000929

Gnomad4 AMR exome AF: 0.00432

Gnomad4 ASJ exome AF: 0.00104

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000778

Gnomad4 FIN exome AF: 0.00105

Gnomad4 NFE exome AF: 0.00736

Gnomad4 OTH exome AF: 0.00572

GnomAD4 genome AF: 0.00418 AC: 637 AN: 152290 Hom.: 2 Cov.: 32 AF XY: 0.00392 AC XY: 292 AN XY: 74472

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00569

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00682

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00463 Hom.: 1

Bravo AF: 0.00467

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	4.5
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs149475648; hg19: chr5-42688957;