17-1270679-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/22 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

Clinical Significance

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

Conservation

PhyloP100: -0.237

Publications

0 publications found

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]

BHLHA9 Gene-Disease associations (from GenCC):

mesoaxial synostotic syndactyly with phalangeal reduction
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
tibial aplasia-ectrodactyly syndrome
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
Camptosynpolydactyly, complex
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
split-hand/foot malformation with long bone deficiency 1
Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

BHLHA9 links:

ENSG00000300095 (HGNC:):

ENSG00000300095 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 501415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 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 GnomAdExome4. There are 195 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR,Unknown,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164405.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BHLHA9	NM_001164405.2	MANE Select	c.116C>A	p.Ala39Glu	missense	Exon 1 of 1	NP_001157877.1	Q7RTU4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BHLHA9	ENST00000391429.2	TSL:6 MANE Select	c.116C>A	p.Ala39Glu	missense	Exon 1 of 1	ENSP00000375248.1	Q7RTU4
ENSG00000300095	ENST00000768751.1		n.-175G>T		upstream_gene	N/A
ENSG00000300095	ENST00000768752.1		n.-178G>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.00443

AC:

673

AN:

152054

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00

AC:

AN:

562

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000416

AC:

486

AN:

1169298

Hom.:

Cov.:

AF XY:

0.000345

AC XY:

195

AN XY:

564690

show subpopulations

African (AFR)

AF:

0.0175

AC:

408

AN:

23326

American (AMR)

AF:

0.00139

AC:

AN:

8656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15700

East Asian (EAS)

AF:

0.00

AC:

AN:

27034

South Asian (SAS)

AF:

0.00

AC:

AN:

39898

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26660

Middle Eastern (MID)

AF:

0.000276

AC:

AN:

3626

European-Non Finnish (NFE)

AF:

0.00000205

AC:

AN:

976560

Other (OTH)

AF:

0.00132

AC:

AN:

47838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

122

153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00446

AC:

678

AN:

152162

Hom.:

Cov.:

AF XY:

0.00394

AC XY:

293

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0156

AC:

646

AN:

41542

American (AMR)

AF:

0.00144

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67946

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

107

142

178

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00319

Hom.:

Bravo

AF:

0.00501

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

5.5

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.0030

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.24

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.43

MutationAssessor

Benign

-1.1

PhyloP100

-0.24

PrimateAI

Uncertain

0.67

PROVEAN

Benign

1.4

REVEL

Benign

0.19

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.064

MVP

0.24

ClinPred

0.029

GERP RS

1.3

PromoterAI

0.013

Neutral

(source)

Varity_R

0.050

gMVP

0.18

Mutation Taster

=99/1

polymorphism

(source)

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

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