17-1270679-C-T

Variant names:

• chr17-1270679-C-T
• rs551239535
• NM_001164405.2:c.116C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164405.2(BHLHA9):​c.116C>T​(p.Ala39Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000855 in 1,169,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A39E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: BHLHA9 NM_001164405.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.237
• Publications: 0 publications found

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

ENSG00000300095 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.084623694).

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>T	p.Ala39Val	missense	Exon 1 of 1	NP_001157877.1	Q7RTU4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BHLHA9	ENST00000391429.2	TSL:6 MANE Select	c.116C>T	p.Ala39Val	missense	Exon 1 of 1	ENSP00000375248.1	Q7RTU4
	ENSG00000300095	ENST00000768751.1		n.-175G>A		upstream_gene	N/A
	ENSG00000300095	ENST00000768752.1		n.-178G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.55e-7 AC: 1 AN: 1169298 Hom.: 0 Cov.: 31 AF XY: 0.00000177 AC XY: 1 AN XY: 564690

African (AFR) AF: 0.00 AC: 0 AN: 23326

American (AMR) AF: 0.00 AC: 0 AN: 8656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15700

East Asian (EAS) AF: 0.00 AC: 0 AN: 27034

South Asian (SAS) AF: 0.0000251 AC: 1 AN: 39898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26660

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3626

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 976560

Other (OTH) AF: 0.00 AC: 0 AN: 47838

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.34	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.085	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.24
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.21
Sift	Benign	0.16	T
Sift4G	Benign	0.27	T
Vest4		0.047
MutPred		0.17		Loss of sheet (P = 0.0228)
MVP		0.21
ClinPred		0.18	T
GERP RS		1.3
PromoterAI		0.0046	Neutral
Varity_R		0.029
gMVP		0.23
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs551239535; hg19: chr17-1173973;