2-176189148-A-G

Position:

• chr2-176189148-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024501.3(HOXD1):​c.347A>G​(p.Asp116Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,436,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: HOXD1 NM_024501.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.06

Genes affected

HOXD1 (HGNC:5132): (homeobox D1) This gene is a member of the Antp homeobox family and encodes a protein with a homeobox DNA-binding domain. This nuclear protein functions as a sequence-specific transcription factor that is involved in differentiation and limb development. Mutations in this gene have been associated with severe developmental defects on the anterior-posterior (a-p) limb axis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXD1	NM_024501.3	c.347A>G	p.Asp116Gly	missense_variant	1/2	ENST00000331462.6	NP_078777.1
HOXD1	XM_047444086.1	c.347A>G	p.Asp116Gly	missense_variant	1/3		XP_047300042.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXD1	ENST00000331462.6	c.347A>G	p.Asp116Gly	missense_variant	1/2	1	NM_024501.3	ENSP00000328598.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436088 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 712498

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: 9.06e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jul 07, 2022

The c.347A>G (p.D116G) alteration is located in exon 1 (coding exon 1) of the HOXD1 gene. This alteration results from a A to G substitution at nucleotide position 347, causing the aspartic acid (D) at amino acid position 116 to be replaced by a glycine (G). 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	0.12
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.046
Eigen_PC	Benign	0.033
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.070	D
MutationAssessor	Uncertain	2.4	M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.17	T
Polyphen		0.95	P
Vest4		0.59
MutPred		0.35		Loss of phosphorylation at Y115 (P = 0.1342);
MVP		0.92
ClinPred		0.87	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.16
gMVP		0.48

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-177053876;