chr17-1270605-G-C

Variant names:

• chr17-1270605-G-C
• NM_001164405.2:c.42G>C

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.42G>C​(p.Lys14Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BHLHA9 NM_001164405.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.515
• 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=0.111780226).

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.42G>C	p.Lys14Asn	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.42G>C	p.Lys14Asn	missense	Exon 1 of 1	ENSP00000375248.1	Q7RTU4
	ENSG00000300095	ENST00000768751.1		n.-101C>G		upstream_gene	N/A
	ENSG00000300095	ENST00000768752.1		n.-104C>G		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.29	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.52
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.098
Sift	Benign	0.091	T
Sift4G	Benign	0.17	T
Vest4		0.085
MutPred		0.24		Loss of ubiquitination at K14 (P = 0.0011)
MVP		0.28
ClinPred		0.034	T
GERP RS		0.33
PromoterAI		-0.0046	Neutral
Varity_R		0.055
gMVP		0.24

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

hg19: chr17-1173899;