rs12521020

Variant names:

• chr5-42565741-C-T
• rs12521020
• NM_000163.5:c.-11-123C>T

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.-11-123C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,576,894 control chromosomes in the GnomAD database, including 64,076 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (10139 hom., cov: 32)
  • Exomes 𝑓: 0.27 (53937 hom.)
• Consequence: GHR NM_000163.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.109
• Publications: 6 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=-0.89).
• BP6: Variant 5-42565741-C-T is Benign according to our data. Variant chr5-42565741-C-T is described in ClinVar as [Benign]. Clinvar id is 1231710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.53 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5	c.-11-123C>T		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.-11-123C>T		intron_variant	Intron 1 of 9	1	NM_000163.5	ENSP00000230882.4

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51931 AN: 151914 Hom.: 10117 Cov.: 32

Gnomad AFR AF: 0.536

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.323

GnomAD4 exome AF: 0.268 AC: 382049 AN: 1424862 Hom.: 53937 Cov.: 32 AF XY: 0.266 AC XY: 188241 AN XY: 706736

African (AFR) AF: 0.545 AC: 17814 AN: 32680

American (AMR) AF: 0.217 AC: 8720 AN: 40116

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 5983 AN: 25408

East Asian (EAS) AF: 0.110 AC: 4207 AN: 38400

South Asian (SAS) AF: 0.220 AC: 18183 AN: 82722

European-Finnish (FIN) AF: 0.321 AC: 15215 AN: 47442

Middle Eastern (MID) AF: 0.304 AC: 1718 AN: 5660

European-Non Finnish (NFE) AF: 0.269 AC: 293905 AN: 1093374

Other (OTH) AF: 0.276 AC: 16304 AN: 59060

GnomAD4 genome AF: 0.342 AC: 51995 AN: 152032 Hom.: 10139 Cov.: 32 AF XY: 0.342 AC XY: 25439 AN XY: 74336

African (AFR) AF: 0.536 AC: 22206 AN: 41442

American (AMR) AF: 0.271 AC: 4143 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 793 AN: 3468

East Asian (EAS) AF: 0.149 AC: 770 AN: 5166

South Asian (SAS) AF: 0.209 AC: 1010 AN: 4822

European-Finnish (FIN) AF: 0.334 AC: 3528 AN: 10568

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.273 AC: 18522 AN: 67960

Other (OTH) AF: 0.321 AC: 678 AN: 2114

Alfa AF: 0.328 Hom.: 1469

Bravo AF: 0.345

Asia WGS AF: 0.192 AC: 668 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.26
DANN	Benign	0.54
PhyloP100		-0.11
PromoterAI		-0.0087	Neutral
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: rs12521020; hg19: chr5-42565843;