rs76254681

Variant names:

• chr5-42711179-A-G
• rs76254681
• NM_000163.5:c.619-28A>G

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.619-28A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.027 in 1,586,480 control chromosomes in the GnomAD database, including 831 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.042 (187 hom., cov: 32)
  • Exomes 𝑓: 0.025 (644 hom.)
• Consequence: GHR NM_000163.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.751
• Publications: 3 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-42711179-A-G is Benign according to our data. Variant chr5-42711179-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.081 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5	c.619-28A>G		intron_variant	Intron 6 of 9	ENST00000230882.9	NP_000154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHR	ENST00000230882.9	c.619-28A>G		intron_variant	Intron 6 of 9	1	NM_000163.5	ENSP00000230882.4

Frequencies

GnomAD3 genomes AF: 0.0422 AC: 6426 AN: 152150 Hom.: 187 Cov.: 32

Gnomad AFR AF: 0.0834

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0397

Gnomad EAS AF: 0.0190

Gnomad SAS AF: 0.0246

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0268

Gnomad OTH AF: 0.0430

GnomAD2 exomes AF: 0.0281 AC: 7050 AN: 251034 AF XY: 0.0281

Gnomad AFR exome AF: 0.0836

Gnomad AMR exome AF: 0.0187

Gnomad ASJ exome AF: 0.0447

Gnomad EAS exome AF: 0.0182

Gnomad FIN exome AF: 0.0148

Gnomad NFE exome AF: 0.0252

Gnomad OTH exome AF: 0.0306

GnomAD4 exome AF: 0.0253 AC: 36328 AN: 1434212 Hom.: 644 Cov.: 27 AF XY: 0.0256 AC XY: 18304 AN XY: 715258

African (AFR) AF: 0.0862 AC: 2826 AN: 32778

American (AMR) AF: 0.0206 AC: 920 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0462 AC: 1198 AN: 25930

East Asian (EAS) AF: 0.0238 AC: 941 AN: 39550

South Asian (SAS) AF: 0.0288 AC: 2469 AN: 85680

European-Finnish (FIN) AF: 0.0148 AC: 787 AN: 53268

Middle Eastern (MID) AF: 0.0650 AC: 371 AN: 5710

European-Non Finnish (NFE) AF: 0.0231 AC: 25070 AN: 1087130

Other (OTH) AF: 0.0294 AC: 1746 AN: 59480

GnomAD4 genome AF: 0.0422 AC: 6433 AN: 152268 Hom.: 187 Cov.: 32 AF XY: 0.0406 AC XY: 3025 AN XY: 74444

African (AFR) AF: 0.0833 AC: 3463 AN: 41552

American (AMR) AF: 0.0323 AC: 494 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0397 AC: 138 AN: 3472

East Asian (EAS) AF: 0.0191 AC: 99 AN: 5186

South Asian (SAS) AF: 0.0246 AC: 119 AN: 4830

European-Finnish (FIN) AF: 0.0142 AC: 151 AN: 10626

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0268 AC: 1824 AN: 68000

Other (OTH) AF: 0.0426 AC: 90 AN: 2114

Alfa AF: 0.0375 Hom.: 29

Bravo AF: 0.0447

Asia WGS AF: 0.0200 AC: 69 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 20, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely 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	-0.84
CADD	Benign	0.29
DANN	Benign	0.65
PhyloP100		0.75
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: 28

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs76254681; hg19: chr5-42711281;