rs536639583

chr2-176092922-G-Cchr2-176092922-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_000523.4(HOXD13):c.32G>C(p.Gly11Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0005 in 1,329,670 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00086 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (4 hom.)
• Consequence: HOXD13 NM_000523.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 0.282

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.118177116).
• BP6: Variant 2-176092922-G-C is Benign according to our data. Variant chr2-176092922-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225651.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000856 (130/151790) while in subpopulation EAS AF= 0.022 (113/5136). AF 95% confidence interval is 0.0187. There are 1 homozygotes in gnomad4. There are 67 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXD13	NM_000523.4	c.32G>C	p.Gly11Ala	missense_variant	1/2	ENST00000392539.4
HOXD13	XM_011511068.3	c.725-1558G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXD13	ENST00000392539.4	c.32G>C	p.Gly11Ala	missense_variant	1/2	1	NM_000523.4	P1

Frequencies

GnomAD3 genomes AF: 0.000857 AC: 130 AN: 151682 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0219

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000185 AC: 7 AN: 37778 Hom.: 0 AF XY: 0.000299 AC XY: 7 AN XY: 23412

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00400

Gnomad SAS exome AF: 0.000660

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000454 AC: 535 AN: 1177880 Hom.: 4 Cov.: 30 AF XY: 0.000438 AC XY: 252 AN XY: 575020

Gnomad4 AFR exome AF: 0.0000429

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0167

Gnomad4 SAS exome AF: 0.000693

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000923

Gnomad4 OTH exome AF: 0.00138

GnomAD4 genome AF: 0.000856 AC: 130 AN: 151790 Hom.: 1 Cov.: 33 AF XY: 0.000903 AC XY: 67 AN XY: 74196

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000263

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0220

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000277 Hom.: 0

Bravo AF: 0.00106

ExAC AF: 0.000528 AC: 8

Asia WGS AF: 0.00499 AC: 17 AN: 3418

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Sep 21, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2018	The G11A variant has been published previously in association with a synpolydactyly phenotype; the homozygous proband was more severely affected than the heterozygous mother, but the father's phenotype was not provided (Brison et al., 2012). However, the variant has also been observed in the homozygous state at GeneDx in an individual whose phenotype did not match a HOXD13 presentation. The variant is observed in 3/1714 (0.175%) alleles from individuals of South Asian background in the ExAC dataset (Lek et al., 2016). G11A is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Functional studies have shown that G11A has no effect on DNA binding, transactivation, or localization; however, it speeds protein degradation and led to skeletal abnormalities in chick embryos (Brison et al., 2012). In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Synpolydactyly type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.060
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.55	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.88	N
REVEL	Uncertain	0.62
Sift	Benign	0.12	T
Sift4G	Benign	0.17	T
Polyphen		0.95	P
Vest4		0.71
MutPred		0.66		Gain of helix (P = 0.0034);
MVP		0.95
ClinPred		0.16	T
GERP RS		2.3
Varity_R		0.13
gMVP		0.39

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: rs536639583; hg19: chr2-176957650;