17-1270679-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001164405.2(BHLHA9):​c.116C>A​(p.Ala39Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000881 in 1,321,460 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0045 ( 8 hom., cov: 33)
Exomes 𝑓: 0.00042 ( 6 hom. )

Consequence

BHLHA9
NM_001164405.2 missense

Scores

2
17

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.237
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.004467815).
BP6
Variant 17-1270679-C-A is Benign according to our data. Variant chr17-1270679-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 501415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-1270679-C-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000416 (486/1169298) while in subpopulation AFR AF= 0.0175 (408/23326). AF 95% confidence interval is 0.0161. There are 6 homozygotes in gnomad4_exome. There are 195 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BHLHA9NM_001164405.2 linkc.116C>A p.Ala39Glu 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.116C>A p.Ala39Glu missense_variant Exon 1 of 1 6 NM_001164405.2 ENSP00000375248.1 Q7RTU4

Frequencies

GnomAD3 genomes
AF:
0.00443
AC:
673
AN:
152054
Hom.:
8
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0155
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00144
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00382
GnomAD4 exome
AF:
0.000416
AC:
486
AN:
1169298
Hom.:
6
Cov.:
31
AF XY:
0.000345
AC XY:
195
AN XY:
564690
show subpopulations
Gnomad4 AFR exome
AF:
0.0175
Gnomad4 AMR exome
AF:
0.00139
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000205
Gnomad4 OTH exome
AF:
0.00132
GnomAD4 genome
AF:
0.00446
AC:
678
AN:
152162
Hom.:
8
Cov.:
33
AF XY:
0.00394
AC XY:
293
AN XY:
74392
show subpopulations
Gnomad4 AFR
AF:
0.0156
Gnomad4 AMR
AF:
0.00144
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00378
Alfa
AF:
0.00319
Hom.:
0
Bravo
AF:
0.00501

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Dec 04, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:1
Apr 11, 2017
Eurofins Ntd Llc (ga)
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.081
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
5.5
DANN
Benign
0.72
DEOGEN2
Benign
0.0030
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.026
N
LIST_S2
Benign
0.24
T
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.0045
T
MetaSVM
Benign
-0.43
T
MutationAssessor
Benign
-1.1
N
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
1.4
N
REVEL
Benign
0.19
Sift
Benign
1.0
T
Sift4G
Benign
1.0
T
Vest4
0.064
MVP
0.24
ClinPred
0.029
T
GERP RS
1.3
Varity_R
0.050
gMVP
0.18

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs551239535; hg19: chr17-1173973; API