2-176092931-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000523.4(HOXD13):c.41C>T(p.Ala14Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,332,590 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (16 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (11 hom.)
• Consequence: HOXD13 NM_000523.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.67

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065018237).
• BP6: Variant 2-176092931-C-T is Benign according to our data. Variant chr2-176092931-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 282381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-176092931-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00831 (1261/151706) while in subpopulation AFR AF= 0.0287 (1190/41492). AF 95% confidence interval is 0.0273. There are 16 homozygotes in gnomad4. There are 614 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXD13	NM_000523.4	c.41C>T	p.Ala14Val	missense_variant	1/2	ENST00000392539.4
HOXD13	XM_011511068.3	c.725-1549C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXD13	ENST00000392539.4	c.41C>T	p.Ala14Val	missense_variant	1/2	1	NM_000523.4	P1

Frequencies

GnomAD3 genomes AF: 0.00821 AC: 1244 AN: 151600 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00361

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.000202 AC: 8 AN: 39590 Hom.: 0 AF XY: 0.000246 AC XY: 6 AN XY: 24426

Gnomad AFR exome AF: 0.00718

Gnomad AMR exome AF: 0.000760

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000104

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000585 AC: 691 AN: 1180884 Hom.: 11 Cov.: 30 AF XY: 0.000505 AC XY: 291 AN XY: 576652

Gnomad4 AFR exome AF: 0.0242

Gnomad4 AMR exome AF: 0.00176

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000642

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000164

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00831 AC: 1261 AN: 151706 Hom.: 16 Cov.: 33 AF XY: 0.00828 AC XY: 614 AN XY: 74156

Gnomad4 AFR AF: 0.0287

Gnomad4 AMR AF: 0.00361

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00203 Hom.: 0

Bravo AF: 0.00878

ExAC AF: 0.000425 AC: 6

Asia WGS AF: 0.00296 AC: 10 AN: 3394

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.99	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.21
Sift	Benign	0.033	D
Sift4G	Uncertain	0.018	D
Polyphen		0.023	B
Vest4		0.36
MVP		0.93
ClinPred		0.022	T
GERP RS		2.8
Varity_R		0.082
gMVP		0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs555136684; hg19: chr2-176957659;