2-176151907-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_014621.3(HOXD4):c.274C>A(p.Pro92Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00052 in 1,594,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (0 hom.)
• Consequence: HOXD4 NM_014621.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.34

Genes affected

HOXD4 (HGNC:5138): (homeobox D4) 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 determining positional values in developing limb buds. Alternatively spliced variants have been described but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.060141206).
• BS2: High AC in GnomAd at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXD4	NM_014621.3	c.274C>A	p.Pro92Thr	missense_variant	1/2	ENST00000306324.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXD4	ENST00000306324.4	c.274C>A	p.Pro92Thr	missense_variant	1/2	1	NM_014621.3	P1
HOXD3	ENST00000432796.2	c.-85+14908C>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.000420 AC: 64 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000426 AC: 88 AN: 206478 Hom.: 0 AF XY: 0.000412 AC XY: 47 AN XY: 114002

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000639

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000508

Gnomad SAS exome AF: 0.000597

Gnomad FIN exome AF: 0.000320

Gnomad NFE exome AF: 0.000588

Gnomad OTH exome AF: 0.000761

GnomAD4 exome AF: 0.000530 AC: 765 AN: 1442652 Hom.: 0 Cov.: 31 AF XY: 0.000536 AC XY: 384 AN XY: 715942

Gnomad4 AFR exome AF: 0.0000606

Gnomad4 AMR exome AF: 0.0000710

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000256

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.000454

Gnomad4 NFE exome AF: 0.000578

Gnomad4 OTH exome AF: 0.000605

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74492

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000470

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000430 Hom.: 0

Bravo AF: 0.000340

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000266 AC: 1

ESP6500EA AF: 0.000517 AC: 4

ExAC AF: 0.000382 AC: 44

Asia WGS AF: 0.00231 AC: 8 AN: 3476

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

Sep 01, 2021

The c.274C>A (p.P92T) alteration is located in exon 1 (coding exon 1) of the HOXD4 gene. This alteration results from a C to A substitution at nucleotide position 274, causing the proline (P) at amino acid position 92 to be replaced by a threonine (T). 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	0.067
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	16
Dann	Benign	0.78
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.71
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.34	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.53	D;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.18
Sift	Benign	0.22	T
Sift4G	Benign	0.14	T
Polyphen		0.015	B
Vest4		0.17
MVP		0.93
MPC		0.47
ClinPred		0.033	T
GERP RS		2.7
Varity_R		0.093
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

LitVar

Other links and lift over

dbSNP: rs376322574; hg19: chr2-177016635;