17-1270814-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_001164405.2(BHLHA9):​c.251C>T​(p.Ala84Val) variant causes a missense change. The variant allele was found at a frequency of 0.000129 in 1,475,800 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A84G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

BHLHA9
NM_001164405.2 missense

Scores

13
4
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.07
Variant links:
Genes affected
BHLHA9 (HGNC:35126): (basic helix-loop-helix family member a9) This gene is a member of the basic helix-loop-helix family. The encoded protein is a transcription factor involved in limb development. Mutations in this gene have been associated with mesoaxial synostotic syndactyly Malik-Percin type (MSSD). Copy number variation of a locus containing this gene has been linked to a form of split-hand/foot malformation with long bone deficiency (SHFLD3). [provided by RefSeq, Mar 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a domain bHLH (size 52) in uniprot entity BHA09_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_001164405.2
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.961

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BHLHA9NM_001164405.2 linkc.251C>T p.Ala84Val missense_variant Exon 1 of 1 ENST00000391429.2 NP_001157877.1 Q7RTU4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BHLHA9ENST00000391429.2 linkc.251C>T p.Ala84Val missense_variant Exon 1 of 1 6 NM_001164405.2 ENSP00000375248.1 Q7RTU4

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
151778
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000236
Gnomad OTH
AF:
0.000481
GnomAD3 exomes
AF:
0.0000738
AC:
6
AN:
81270
Hom.:
0
AF XY:
0.0000862
AC XY:
4
AN XY:
46382
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000116
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000102
Gnomad OTH exome
AF:
0.000418
GnomAD4 exome
AF:
0.000128
AC:
169
AN:
1324022
Hom.:
1
Cov.:
32
AF XY:
0.000138
AC XY:
90
AN XY:
652910
show subpopulations
Gnomad4 AFR exome
AF:
0.000223
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000388
Gnomad4 SAS exome
AF:
0.0000953
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000128
Gnomad4 OTH exome
AF:
0.000182
GnomAD4 genome
AF:
0.000138
AC:
21
AN:
151778
Hom.:
0
Cov.:
33
AF XY:
0.0000810
AC XY:
6
AN XY:
74118
show subpopulations
Gnomad4 AFR
AF:
0.0000725
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000236
Gnomad4 OTH
AF:
0.000481
Bravo
AF:
0.000140

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Nov 21, 2019
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.88
D
Eigen
Uncertain
0.20
Eigen_PC
Benign
0.12
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
D
M_CAP
Pathogenic
0.69
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.1
M
PrimateAI
Pathogenic
0.86
D
PROVEAN
Uncertain
-4.0
D
REVEL
Pathogenic
0.87
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Vest4
0.86
MutPred
0.80
Loss of disorder (P = 0.064);
MVP
0.54
ClinPred
0.88
D
GERP RS
3.9
Varity_R
0.93
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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

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

Other links and lift over

dbSNP: rs964527970; hg19: chr17-1174108; API