17-1270781-G-A

Variant names:

• chr17-1270781-G-A
• rs672601338
• NM_001164405.2:c.218G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_001164405.2(BHLHA9):​c.218G>A​(p.Arg73Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000152 in 1,317,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R73L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: BHLHA9 NM_001164405.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.95
• 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: 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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001164405.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-1270781-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3065871.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962

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.218G>A	p.Arg73Gln	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.218G>A	p.Arg73Gln	missense	Exon 1 of 1	ENSP00000375248.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000152 AC: 2 AN: 1317564 Hom.: 0 Cov.: 31 AF XY: 0.00000154 AC XY: 1 AN XY: 649630

African (AFR) AF: 0.00 AC: 0 AN: 26744

American (AMR) AF: 0.00 AC: 0 AN: 26870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23172

East Asian (EAS) AF: 0.00 AC: 0 AN: 28134

South Asian (SAS) AF: 0.00 AC: 0 AN: 72432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32760

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5288

European-Non Finnish (NFE) AF: 0.00000191 AC: 2 AN: 1047560

Other (OTH) AF: 0.00 AC: 0 AN: 54604

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.83
MutPred		0.80		Gain of ubiquitination at K76 (P = 0.0328)
MVP		0.82
ClinPred		1.0	D
GERP RS		4.8
PromoterAI		0.026	Neutral
Varity_R		0.84
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs672601338; hg19: chr17-1174075;