2-176171813-G-C

Position:

• chr2-176171813-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006898.5(HOXD3):​c.838G>C​(p.Val280Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,459,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: HOXD3 NM_006898.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.84

Genes affected

HOXD3 (HGNC:5137): (homeobox D3) 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 at 2q31-2q37 chromosome regions. Deletions that removed the entire HOXD gene cluster or 5' end of this cluster have been associated with severe limb and genital abnormalities. The protein encoded by this gene may play a role in the regulation of cell adhesion processes. [provided by RefSeq, Jul 2008]

HAGLR (HGNC:43755): (HOXD antisense growth-associated long non-coding RNA)

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13637096).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXD3	NM_006898.5	c.838G>C	p.Val280Leu	missense_variant	4/4	ENST00000683222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXD3	ENST00000683222.1	c.838G>C	p.Val280Leu	missense_variant	4/4		NM_006898.5	P1
HOXD3	ENST00000249440.4	c.838G>C	p.Val280Leu	missense_variant	3/3	1		P1
HOXD3	ENST00000410016.5	c.838G>C	p.Val280Leu	missense_variant	3/3	5		P1
HAGLR	ENST00000413969.6	n.406+4722C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459378 Hom.: 0 Cov.: 36 AF XY: 0.00000551 AC XY: 4 AN XY: 725904

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2022

The c.838G>C (p.V280L) alteration is located in exon 3 (coding exon 2) of the HOXD3 gene. This alteration results from a G to C substitution at nucleotide position 838, causing the valine (V) at amino acid position 280 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.70	.;T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	0.76	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.040	N;N
REVEL	Benign	0.22
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0020	B;B
Vest4		0.082
MutPred		0.19		Loss of catalytic residue at V280 (P = 0.2263);Loss of catalytic residue at V280 (P = 0.2263);
MVP		0.82
ClinPred		0.58	D
GERP RS		5.3
Varity_R		0.14
gMVP		0.55

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: rs748868145; hg19: chr2-177036541;