Variant 2-176169487-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006898.5(HOXD3):c.373A>C(p.Thr125Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

HOXD3
NM_006898.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.894

Variant links:

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]

HOXD3 links:

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

HAGLR links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07256612).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXD3	NM_006898.5 linkuse as main transcript	c.373A>C	p.Thr125Pro	missense_variant	3/4	ENST00000683222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HOXD3	ENST00000683222.1 linkuse as main transcript	c.373A>C	p.Thr125Pro	missense_variant	3/4		NM_006898.5	P1
HOXD3	ENST00000249440.4 linkuse as main transcript	c.373A>C	p.Thr125Pro	missense_variant	2/3	1		P1
HOXD3	ENST00000410016.5 linkuse as main transcript	c.373A>C	p.Thr125Pro	missense_variant	2/3	5		P1
HAGLR	ENST00000413969.6 linkuse as main transcript	n.407-5378T>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.373A>C (p.T125P) alteration is located in exon 2 (coding exon 1) of the HOXD3 gene. This alteration results from a A to C substitution at nucleotide position 373, causing the threonine (T) at amino acid position 125 to be replaced by a proline (P). 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

0.060

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.20

T;T

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.39

.;T

M_CAP

Benign

0.051

MetaRNN

Benign

0.073

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.55

N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.14

Sift

Benign

0.44

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.0

B;B

Vest4

0.16

MutPred

0.31

Loss of phosphorylation at T125 (P = 0.0034);Loss of phosphorylation at T125 (P = 0.0034);

MVP

0.87

ClinPred

0.11

GERP RS

2.8

Varity_R

0.11

gMVP

0.27

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over