17-1270774-A-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_001164405.2(BHLHA9):c.211A>G(p.Asn71Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

BHLHA9
NM_001164405.2 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 7.42

Publications

3 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: Orphanet, G2P, 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001164405.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 17-1270774-A-G is Pathogenic according to our data. Variant chr17-1270774-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 162065.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BHLHA9	NM_001164405.2	MANE Select	c.211A>G	p.Asn71Asp	missense	Exon 1 of 1	NP_001157877.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BHLHA9	ENST00000391429.2	TSL:6 MANE Select	c.211A>G	p.Asn71Asp	missense	Exon 1 of 1	ENSP00000375248.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1314482

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

648148

African (AFR)

AF:

0.00

AC:

AN:

26670

American (AMR)

AF:

0.00

AC:

AN:

26400

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23066

East Asian (EAS)

AF:

0.00

AC:

AN:

28040

South Asian (SAS)

AF:

0.00

AC:

AN:

72028

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32716

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5228

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1045918

Other (OTH)

AF:

0.00

AC:

AN:

54416

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Mesoaxial synostotic syndactyly with phalangeal reduction

Pathogenic:2

Dec 04, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Oct 16, 2014

Human Genetics, Philipps Universitaet Marburg

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.2

MutationAssessor

Pathogenic

3.0

PhyloP100

7.4

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.81

MutPred

0.77

Gain of ubiquitination at K76 (P = 0.0314)

MVP

0.83

ClinPred

1.0

GERP RS

4.8

PromoterAI

0.053

Neutral

(source)

Varity_R

0.96

gMVP

0.78

Mutation Taster

=18/82

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over