chr2-176093013-C-T

Variant names:

• chr2-176093013-C-T
• rs1449052028
• NM_000523.4:c.123C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_000523.4(HOXD13):​c.123C>T​(p.Arg41Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000081 in 1,234,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: HOXD13 NM_000523.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.147
• Publications: 0 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, Laboratory for Molecular Medicine, G2P
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 2-176093013-C-T is Benign according to our data. Variant chr2-176093013-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3649008.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.147 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000523.4. 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
	HOXD13	NM_000523.4	MANE Select	c.123C>T	p.Arg41Arg	synonymous	Exon 1 of 2	NP_000514.2	P35453

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXD13	ENST00000392539.4	TSL:1 MANE Select	c.123C>T	p.Arg41Arg	synonymous	Exon 1 of 2	ENSP00000376322.3	P35453

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 8.10e-7 AC: 1 AN: 1234870 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 606132

African (AFR) AF: 0.00 AC: 0 AN: 24142

American (AMR) AF: 0.00 AC: 0 AN: 13960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19448

East Asian (EAS) AF: 0.00 AC: 0 AN: 26884

South Asian (SAS) AF: 0.0000178 AC: 1 AN: 56102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4598

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1009002

Other (OTH) AF: 0.00 AC: 0 AN: 50340

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	13
DANN	Benign	0.96
PhyloP100		0.15
PromoterAI		0.0055	Neutral
Mutation Taster		=100/0	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: rs1449052028; hg19: chr2-176957741;