Genetic Variant BHLHA9:p.Pro52Leu (chr17-1270718-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001164405.2(BHLHA9):c.155C>T(p.Pro52Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000924 in 1,190,560 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P52R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000092 ( 0 hom. )

Consequence

BHLHA9
NM_001164405.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.854

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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08826882).

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.155C>T	p.Pro52Leu	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.155C>T	p.Pro52Leu	missense	Exon 1 of 1	ENSP00000375248.1	Q7RTU4
ENSG00000300095	ENST00000768751.1		n.-214G>A		upstream_gene	N/A
ENSG00000300095	ENST00000768752.1		n.-217G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000924

AC:

AN:

1190560

Hom.:

Cov.:

AF XY:

0.00000691

AC XY:

AN XY:

578616

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23660

American (AMR)

AF:

0.00

AC:

AN:

9508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16334

East Asian (EAS)

AF:

0.00

AC:

AN:

27152

South Asian (SAS)

AF:

0.00

AC:

AN:

45000

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27686

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3944

European-Non Finnish (NFE)

AF:

0.0000101

AC:

AN:

988568

Other (OTH)

AF:

0.0000205

AC:

AN:

48708

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Benign

-0.30

CADD

Benign

1.8

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.012

Eigen

Benign

-0.89

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.51

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.088

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

0.34

PhyloP100

0.85

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.26

REVEL

Benign

0.12

Sift

Benign

0.29

Sift4G

Benign

0.81

Vest4

0.055

MutPred

0.30

Gain of MoRF binding (P = 0.0601)

MVP

0.58

ClinPred

0.11

GERP RS

-3.2

PromoterAI

-0.0089

Neutral

(source)

Varity_R

0.039

gMVP

0.30

Mutation Taster

=94/6

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over