chrX-84321930-C-A

Variant names:

• chrX-84321930-C-A
• rs377357943
• NM_001177479.2:c.2032G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001177479.2(HDX):​c.2032G>T​(p.Val678Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000759 in 1,185,100 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.0000047 (0 hom. 1 hem.)
• Consequence: HDX NM_001177479.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.792
• Publications: 0 publications found

Genes affected

HDX (HGNC:26411): (highly divergent homeobox) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03590229).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177479.2. 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
	HDX	NM_001177479.2	MANE Select	c.2032G>T	p.Val678Leu	missense	Exon 11 of 11	NP_001170950.1	Q7Z353-1
	HDX	NM_144657.5		c.2032G>T	p.Val678Leu	missense	Exon 10 of 10	NP_653258.2
	HDX	NM_001177478.2		c.1858G>T	p.Val620Leu	missense	Exon 10 of 10	NP_001170949.1	Q7Z353-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDX	ENST00000373177.3	TSL:1 MANE Select	c.2032G>T	p.Val678Leu	missense	Exon 11 of 11	ENSP00000362272.2	Q7Z353-1
	HDX	ENST00000297977.9	TSL:1	c.2032G>T	p.Val678Leu	missense	Exon 10 of 10	ENSP00000297977.5	Q7Z353-1
	HDX	ENST00000851225.1		c.2032G>T	p.Val678Leu	missense	Exon 11 of 11	ENSP00000521284.1

Frequencies

GnomAD3 genomes AF: 0.0000361 AC: 4 AN: 110880 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000762

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000174 AC: 3 AN: 172499 AF XY: 0.0000170

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000388

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000465 AC: 5 AN: 1074220 Hom.: 0 Cov.: 23 AF XY: 0.00000292 AC XY: 1 AN XY: 342706

African (AFR) AF: 0.00 AC: 0 AN: 25703

American (AMR) AF: 0.00 AC: 0 AN: 34377

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18951

East Asian (EAS) AF: 0.00 AC: 0 AN: 29693

South Asian (SAS) AF: 0.00 AC: 0 AN: 51994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4060

European-Non Finnish (NFE) AF: 0.00000607 AC: 5 AN: 824042

Other (OTH) AF: 0.00 AC: 0 AN: 45120

GnomAD4 genome AF: 0.0000361 AC: 4 AN: 110880 Hom.: 0 Cov.: 22 AF XY: 0.0000299 AC XY: 1 AN XY: 33396

African (AFR) AF: 0.00 AC: 0 AN: 30723

American (AMR) AF: 0.00 AC: 0 AN: 10373

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2618

East Asian (EAS) AF: 0.00 AC: 0 AN: 3556

South Asian (SAS) AF: 0.00 AC: 0 AN: 2689

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6031

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000762 AC: 4 AN: 52476

Other (OTH) AF: 0.00 AC: 0 AN: 1489

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00000824 AC: 1

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	0.097
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	14
DANN	Benign	0.78
DEOGEN2	Benign	0.021	T
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.23	N
PhyloP100		0.79
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.75	N
REVEL	Benign	0.056
Sift	Benign	0.64	T
Sift4G	Benign	0.82	T
Polyphen		0.0	B
Vest4		0.057
MutPred		0.078		Loss of sheet (P = 0.1158)
MVP		0.18
MPC		0.12
ClinPred		0.054	T
GERP RS		2.2
Varity_R		0.053
gMVP		0.046
Mutation Taster		=94/6	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: rs377357943; hg19: chrX-83576938;