17-1270496-A-G

Variant names:

• chr17-1270496-A-G
• rs2063188
• NM_001164405.2:c.-68A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164405.2(BHLHA9):​c.-68A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 927,912 control chromosomes in the GnomAD database, including 24,348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6157 hom., cov: 33)
  • Exomes 𝑓: 0.21 (18191 hom.)
• Consequence: BHLHA9 NM_001164405.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.398
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-1270496-A-G is Benign according to our data. Variant chr17-1270496-A-G is described in ClinVar as Benign. ClinVar VariationId is 1262831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

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.-68A>G		5_prime_UTR	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.-68A>G		5_prime_UTR	Exon 1 of 1	ENSP00000375248.1	Q7RTU4
	ENSG00000300095	ENST00000768751.1		n.9T>C		non_coding_transcript_exon	Exon 1 of 2
	ENSG00000300095	ENST00000768752.1		n.6T>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41271 AN: 151948 Hom.: 6145 Cov.: 33

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.267

GnomAD4 exome AF: 0.208 AC: 161716 AN: 775846 Hom.: 18191 AF XY: 0.206 AC XY: 77027 AN XY: 373126

African (AFR) AF: 0.358 AC: 6025 AN: 16816

American (AMR) AF: 0.378 AC: 3027 AN: 8010

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 2172 AN: 12512

East Asian (EAS) AF: 0.425 AC: 10558 AN: 24840

South Asian (SAS) AF: 0.229 AC: 3745 AN: 16372

European-Finnish (FIN) AF: 0.284 AC: 6224 AN: 21938

Middle Eastern (MID) AF: 0.171 AC: 422 AN: 2470

European-Non Finnish (NFE) AF: 0.191 AC: 121855 AN: 638842

Other (OTH) AF: 0.226 AC: 7688 AN: 34046

GnomAD4 genome AF: 0.272 AC: 41330 AN: 152066 Hom.: 6157 Cov.: 33 AF XY: 0.278 AC XY: 20699 AN XY: 74336

African (AFR) AF: 0.357 AC: 14847 AN: 41538

American (AMR) AF: 0.355 AC: 5420 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 603 AN: 3472

East Asian (EAS) AF: 0.415 AC: 2122 AN: 5112

South Asian (SAS) AF: 0.224 AC: 1082 AN: 4826

European-Finnish (FIN) AF: 0.295 AC: 3126 AN: 10600

Middle Eastern (MID) AF: 0.216 AC: 63 AN: 292

European-Non Finnish (NFE) AF: 0.196 AC: 13349 AN: 67942

Other (OTH) AF: 0.267 AC: 564 AN: 2116

Alfa AF: 0.224 Hom.: 627

Bravo AF: 0.283

Asia WGS AF: 0.343 AC: 1187 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.5
DANN	Benign	0.25
PhyloP100		-0.40
PromoterAI		0.00020	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs2063188; hg19: chr17-1173790;