chr5-42424601-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000163.5(GHR):​c.-12+646A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00073 in 1,534,386 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0039 ( 4 hom., cov: 32)
Exomes 𝑓: 0.00038 ( 3 hom. )

Consequence

GHR
NM_000163.5 intron

Scores

2
Splicing: ADA: 0.9199
2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.306
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 5-42424601-A-T is Benign according to our data. Variant chr5-42424601-A-T is described in ClinVar as [Benign]. Clinvar id is 3035850.Status of the report is no_assertion_criteria_provided, 0 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00393 (598/152272) while in subpopulation AFR AF= 0.014 (580/41576). AF 95% confidence interval is 0.013. There are 4 homozygotes in gnomad4. There are 261 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GHRNM_000163.5 linkuse as main transcriptc.-12+646A>T intron_variant ENST00000230882.9
GHRNM_001242399.2 linkuse as main transcriptc.10+3A>T splice_donor_region_variant, intron_variant
GHRNM_001242400.2 linkuse as main transcriptc.-297+3A>T splice_donor_region_variant, intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GHRENST00000230882.9 linkuse as main transcriptc.-12+646A>T intron_variant 1 NM_000163.5 P1P10912-1
GHRENST00000615111.4 linkuse as main transcriptc.-297+3A>T splice_donor_region_variant, intron_variant 5 P1P10912-1
GHRENST00000620156.4 linkuse as main transcriptc.10+3A>T splice_donor_region_variant, intron_variant 5
GHRENST00000513671.5 linkuse as main transcriptc.-12+3A>T splice_donor_region_variant, intron_variant, NMD_transcript_variant 4

Frequencies

GnomAD3 genomes
AF:
0.00391
AC:
595
AN:
152154
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0139
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000916
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00192
GnomAD3 exomes
AF:
0.000749
AC:
96
AN:
128114
Hom.:
0
AF XY:
0.000585
AC XY:
41
AN XY:
70142
show subpopulations
Gnomad AFR exome
AF:
0.0143
Gnomad AMR exome
AF:
0.000328
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000250
GnomAD4 exome
AF:
0.000378
AC:
522
AN:
1382114
Hom.:
3
Cov.:
29
AF XY:
0.000315
AC XY:
215
AN XY:
682058
show subpopulations
Gnomad4 AFR exome
AF:
0.0148
Gnomad4 AMR exome
AF:
0.000364
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000379
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000464
Gnomad4 OTH exome
AF:
0.000588
GnomAD4 genome
AF:
0.00393
AC:
598
AN:
152272
Hom.:
4
Cov.:
32
AF XY:
0.00351
AC XY:
261
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.0140
Gnomad4 AMR
AF:
0.000915
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00190
Alfa
AF:
0.00201
Hom.:
0
Bravo
AF:
0.00459
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

GHR-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 31, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
CADD
Benign
13
DANN
Benign
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.92
dbscSNV1_RF
Benign
0.52
SpliceAI score (max)
0.42
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.42
Position offset: -41

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs116297749; hg19: chr5-42424703; API