2-176151875-A-T

Variant summary

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

The NM_014621.3(HOXD4):c.242A>T(p.Glu81Val) variant causes a missense change. The variant allele was found at a frequency of 0.00143 in 1,585,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (0 hom.)
• Consequence: HOXD4 NM_014621.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 6.80

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21931592).
• BS2: High AC in GnomAd at 130 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXD4	NM_014621.3	c.242A>T	p.Glu81Val	missense_variant	1/2	ENST00000306324.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXD4	ENST00000306324.4	c.242A>T	p.Glu81Val	missense_variant	1/2	1	NM_014621.3	P1
HOXD3	ENST00000432796.2	c.-85+14876A>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.000855 AC: 130 AN: 152082 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000791 AC: 152 AN: 192114 Hom.: 0 AF XY: 0.000710 AC XY: 75 AN XY: 105706

Gnomad AFR exome AF: 0.000100

Gnomad AMR exome AF: 0.000443

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00128

Gnomad NFE exome AF: 0.00139

Gnomad OTH exome AF: 0.000991

GnomAD4 exome AF: 0.00149 AC: 2131 AN: 1433096 Hom.: 0 Cov.: 31 AF XY: 0.00141 AC XY: 999 AN XY: 710238

Gnomad4 AFR exome AF: 0.0000610

Gnomad4 AMR exome AF: 0.000493

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000742

Gnomad4 NFE exome AF: 0.00181

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.000854 AC: 130 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.000632 AC XY: 47 AN XY: 74412

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00163

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00100 Hom.: 0

Bravo AF: 0.000774

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ExAC AF: 0.000583 AC: 65

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Leukemia, acute lymphoblastic, susceptibility to Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.040
Cadd	Benign	22
Dann	Benign	0.67
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.46
Sift	Benign	0.24	T
Sift4G	Benign	0.26	T
Polyphen		0.11	B
Vest4		0.80
MVP		0.87
MPC		0.50
ClinPred		0.058	T
GERP RS		3.1
Varity_R		0.15
gMVP		0.41

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: rs104893636; hg19: chr2-177016603;