rs886037856

Variant names:

• chr17-1270783-GA-TT
• rs886037856
• NM_001164405.2:c.220_221delGAinsTT

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1 PM1 PM2 PP3 PP5_Moderate

The NM_001164405.2(BHLHA9):​c.220_221delGAinsTT​(p.Glu74Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BHLHA9 NM_001164405.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.02

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS1: Transcript NM_001164405.2 (BHLHA9) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a domain bHLH (size 52) in uniprot entity BHA09_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001164405.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 17-1270783-GA-TT is Pathogenic according to our data. Variant chr17-1270783-GA-TT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 253164.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BHLHA9	NM_001164405.2	c.220_221delGAinsTT	p.Glu74Leu	missense_variant		ENST00000391429.2	NP_001157877.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BHLHA9	ENST00000391429.2	c.220_221delGAinsTT	p.Glu74Leu	missense_variant		6	NM_001164405.2	ENSP00000375248.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Camptosynpolydactyly, complex Pathogenic:2

Jan 01, 2015

Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 11, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886037856; hg19: chr17-1174077;