dbSNP rs201804261: GHR:c.-10T>C (chr5-42565865-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000163.5(GHR):c.-10T>C variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000337 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

GHR
NM_000163.5 splice_region

Scores

Splicing: ADA: 0.02335

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.70

Publications

0 publications found

Variant links:

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, G2P, Labcorp Genetics (formerly Invitae)
short stature due to partial GHR deficiency
Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

GHR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000163.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GHR	NM_000163.5	MANE Select	c.-10T>C	splice_region	Exon 2 of 10	NP_000154.1	P10912-1
GHR	NM_000163.5	MANE Select	c.-10T>C	5_prime_UTR	Exon 2 of 10	NP_000154.1	P10912-1
GHR	NM_001242400.2		c.-10T>C	splice_region	Exon 3 of 11	NP_001229329.1	P10912-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GHR	ENST00000230882.9	TSL:1 MANE Select	c.-10T>C	splice_region	Exon 2 of 10	ENSP00000230882.4	P10912-1
GHR	ENST00000230882.9	TSL:1 MANE Select	c.-10T>C	5_prime_UTR	Exon 2 of 10	ENSP00000230882.4	P10912-1
GHR	ENST00000537449.5	TSL:5	c.-10T>C	splice_region	Exon 2 of 10	ENSP00000442206.2	P10912-1

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000577

AC:

145

AN:

251490

AF XY:

0.000552

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.0110

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000193

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000335

AC:

490

AN:

1461656

Hom.:

Cov.:

AF XY:

0.000338

AC XY:

246

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33472

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0106

AC:

278

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000145

AC:

161

AN:

1111812

Other (OTH)

AF:

0.000596

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

118

147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000355

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41546

American (AMR)

AF:

0.000261

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00806

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000696

Hom.:

Bravo

AF:

0.000370

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Laron-type isolated somatotropin defect (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

1.7

PromoterAI

0.014

Neutral

(source)

Mutation Taster

=293/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.023

dbscSNV1_RF

Benign

0.22

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over