2-176092791-C-A

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 53 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXD13	NM_000523.4	c.-100C>A		5_prime_UTR_variant	1/2	ENST00000392539.4
HOXD13	XM_011511068.3	c.725-1689C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXD13	ENST00000392539.4	c.-100C>A		5_prime_UTR_variant	1/2	1	NM_000523.4	P1

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

Gnomad4 AFR exome AF: 0.00365

Gnomad4 AMR exome AF: 0.0135

Gnomad4 ASJ exome AF: 0.0217

Gnomad4 EAS exome AF: 0.00158

Gnomad4 SAS exome AF: 0.0233

Gnomad4 FIN exome AF: 0.0422

Gnomad4 NFE exome AF: 0.0298

Gnomad4 OTH exome AF: 0.0258

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

Gnomad4 AFR AF: 0.00518

Gnomad4 AMR AF: 0.0100

Gnomad4 ASJ AF: 0.0253

Gnomad4 EAS AF: 0.000585

Gnomad4 SAS AF: 0.0215

Gnomad4 FIN AF: 0.0455

Gnomad4 NFE AF: 0.0304

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0257 Hom.: 9

Bravo AF: 0.0175

Asia WGS AF: 0.00755 AC: 26 AN: 3458

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 13, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	18
Dann	Benign	0.90

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs72923424; hg19: chr2-176957519;