rs847194

Variant names:

• chr2-176093973-A-C
• rs847194
• NM_000523.4:c.781+302A>C

Variant summary

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

The NM_000523.4(HOXD13):​c.781+302A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 152,018 control chromosomes in the GnomAD database, including 14,120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.38 (14120 hom., cov: 32)
• Consequence: HOXD13 NM_000523.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.02
• Publications: 3 publications found

Genes affected

HOXD13 (HGNC:5136): (homeobox D13) This gene belongs to the homeobox family of genes. The homeobox genes encode a highly conserved family of transcription factors that play an important role in morphogenesis in all multicellular organisms. Mammals possess four similar homeobox gene clusters, HOXA, HOXB, HOXC and HOXD, located on different chromosomes, consisting of 9 to 11 genes arranged in tandem. This gene is one of several homeobox HOXD genes located in a cluster on chromosome 2. Deletions that remove the entire HOXD gene cluster or the 5' end of this cluster have been associated with severe limb and genital abnormalities. Mutations in this particular gene cause synpolydactyly. [provided by RefSeq, Jul 2008]

HOXD13 Gene-Disease associations (from GenCC):

• brachydactyly-syndactyly syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Laboratory for Molecular Medicine
• synpolydactyly type 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• brachydactyly type E

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• syndactyly type 5

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-176093973-A-C is Benign according to our data. Variant chr2-176093973-A-C is described in ClinVar as Benign. ClinVar VariationId is 1260461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXD13	NM_000523.4	c.781+302A>C		intron_variant	Intron 1 of 1	ENST00000392539.4	NP_000514.2
HOXD13	XM_011511068.3	c.725-507A>C		intron_variant	Intron 1 of 1		XP_011509370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXD13	ENST00000392539.4	c.781+302A>C		intron_variant	Intron 1 of 1	1	NM_000523.4	ENSP00000376322.3

Frequencies

GnomAD3 genomes AF: 0.375 AC: 57021 AN: 151900 Hom.: 14072 Cov.: 32

Gnomad AFR AF: 0.710

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.299

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.343

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

GnomAD4 genome AF: 0.376 AC: 57128 AN: 152018 Hom.: 14120 Cov.: 32 AF XY: 0.371 AC XY: 27560 AN XY: 74306

African (AFR) AF: 0.710 AC: 29408 AN: 41430

American (AMR) AF: 0.309 AC: 4718 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 962 AN: 3472

East Asian (EAS) AF: 0.332 AC: 1712 AN: 5162

South Asian (SAS) AF: 0.379 AC: 1828 AN: 4818

European-Finnish (FIN) AF: 0.157 AC: 1656 AN: 10574

Middle Eastern (MID) AF: 0.291 AC: 85 AN: 292

European-Non Finnish (NFE) AF: 0.235 AC: 15969 AN: 67970

Other (OTH) AF: 0.347 AC: 729 AN: 2102

Alfa AF: 0.313 Hom.: 9369

Bravo AF: 0.399

Asia WGS AF: 0.393 AC: 1371 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.25
DANN	Benign	0.38
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs847194; hg19: chr2-176958701; COSMIC: COSV107502495;