2-176107728-A-T

Variant names:

• chr2-176107728-A-T
• rs907090820
• NM_021192.3:c.373A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_021192.3(HOXD11):​c.373A>T​(p.Met125Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000267 in 1,161,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: HOXD11 NM_021192.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.77
• Publications: 0 publications found

Genes affected

HOXD11 (HGNC:5134): (homeobox D11) 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 in a cluster on chromosome 2. Deletions that remove the entire HOXD gene cluster or the 5' end of this cluster have been associated with severe limb and genital abnormalities. The product of the mouse Hoxd11 gene plays a role in forelimb morphogenesis. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2435576).
• BS2: High AC in GnomAd4 at 24 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021192.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXD11	NM_021192.3	MANE Select	c.373A>T	p.Met125Leu	missense	Exon 1 of 2	NP_067015.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXD11	ENST00000249504.7	TSL:3 MANE Select	c.373A>T	p.Met125Leu	missense	Exon 1 of 2	ENSP00000249504.5	P31277
	HOXD11	ENST00000498438.1	TSL:1	n.412-1179A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 24 AN: 146228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000443

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000678

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000757

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000689 AC: 7 AN: 1015748 Hom.: 0 Cov.: 33 AF XY: 0.00000830 AC XY: 4 AN XY: 482066

African (AFR) AF: 0.000148 AC: 3 AN: 20220

American (AMR) AF: 0.00 AC: 0 AN: 5926

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10930

East Asian (EAS) AF: 0.00 AC: 0 AN: 19774

South Asian (SAS) AF: 0.00 AC: 0 AN: 19200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2532

European-Non Finnish (NFE) AF: 0.00000454 AC: 4 AN: 881514

Other (OTH) AF: 0.00 AC: 0 AN: 38410

GnomAD4 genome AF: 0.000164 AC: 24 AN: 146228 Hom.: 0 Cov.: 32 AF XY: 0.000183 AC XY: 13 AN XY: 71198

African (AFR) AF: 0.000443 AC: 18 AN: 40616

American (AMR) AF: 0.0000678 AC: 1 AN: 14748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3404

East Asian (EAS) AF: 0.00 AC: 0 AN: 4860

South Asian (SAS) AF: 0.00 AC: 0 AN: 4656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000757 AC: 5 AN: 66078

Other (OTH) AF: 0.00 AC: 0 AN: 2030

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000181

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.85
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.8
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.11
Sift	Benign	0.11	T
Sift4G	Benign	0.56	T
Polyphen		0.51	P
Vest4		0.50
MutPred		0.30		Loss of catalytic residue at M125 (P = 0.2725)
MVP		0.45
ClinPred		0.33	T
GERP RS		2.3
PromoterAI		-0.0070	Neutral
Varity_R		0.27
gMVP		0.32
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs907090820; hg19: chr2-176972456;