NM_000523.4:c.-100C>A

Variant names:

• chr2-176092791-C-A
• rs72923424
• NM_000523.4:c.-100C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_000523.4(HOXD13):​c.-100C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0266 in 781,692 control chromosomes in the GnomAD database, including 327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.021 (53 hom., cov: 33)
  • Exomes 𝑓: 0.028 (274 hom.)
• Consequence: HOXD13 NM_000523.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.677
• 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: G2P, Laboratory for Molecular Medicine, Orphanet
• synpolydactyly type 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 2-176092791-C-A is Benign according to our data. Variant chr2-176092791-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1205586.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0207 (3152/152062) while in subpopulation NFE AF = 0.0304 (2066/67950). AF 95% confidence interval is 0.0293. There are 53 homozygotes in GnomAd4. There are 1551 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3152 AD gene.

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.-100C>A		5_prime_UTR	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.-100C>A		5_prime_UTR	Exon 1 of 2	ENSP00000376322.3	P35453

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3154 AN: 151954 Hom.: 53 Cov.: 33

Gnomad AFR AF: 0.00519

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.0253

Gnomad EAS AF: 0.000583

Gnomad SAS AF: 0.0213

Gnomad FIN AF: 0.0455

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.0304

Gnomad OTH AF: 0.0163

GnomAD4 exome AF: 0.0280 AC: 17660 AN: 629630 Hom.: 274 AF XY: 0.0282 AC XY: 8582 AN XY: 304628

African (AFR) AF: 0.00365 AC: 49 AN: 13428

American (AMR) AF: 0.0135 AC: 89 AN: 6574

Ashkenazi Jewish (ASJ) AF: 0.0217 AC: 217 AN: 10016

East Asian (EAS) AF: 0.00158 AC: 35 AN: 22124

South Asian (SAS) AF: 0.0233 AC: 257 AN: 11034

European-Finnish (FIN) AF: 0.0422 AC: 833 AN: 19746

Middle Eastern (MID) AF: 0.0187 AC: 36 AN: 1920

European-Non Finnish (NFE) AF: 0.0298 AC: 15437 AN: 517408

Other (OTH) AF: 0.0258 AC: 707 AN: 27380

GnomAD4 genome AF: 0.0207 AC: 3152 AN: 152062 Hom.: 53 Cov.: 33 AF XY: 0.0209 AC XY: 1551 AN XY: 74322

African (AFR) AF: 0.00518 AC: 215 AN: 41526

American (AMR) AF: 0.0100 AC: 153 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 88 AN: 3472

East Asian (EAS) AF: 0.000585 AC: 3 AN: 5132

South Asian (SAS) AF: 0.0215 AC: 104 AN: 4826

European-Finnish (FIN) AF: 0.0455 AC: 480 AN: 10552

Middle Eastern (MID) AF: 0.00690 AC: 2 AN: 290

European-Non Finnish (NFE) AF: 0.0304 AC: 2066 AN: 67950

Other (OTH) AF: 0.0161 AC: 34 AN: 2110

Alfa AF: 0.0257 Hom.: 9

Bravo AF: 0.0175

Asia WGS AF: 0.00755 AC: 26 AN: 3458

ClinVar

ClinVar submissions as Germline

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	-0.40
CADD	Benign	18
DANN	Benign	0.90
PhyloP100		0.68
PromoterAI		-0.15	Neutral

Splicing

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

Other links and lift over

dbSNP: rs72923424; hg19: chr2-176957519;