NM_001177479.2:c.1682C>T

Variant names:

• chrX-84336859-G-A
• rs762465994
• NM_001177479.2:c.1682C>T

Variant summary

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

The NM_001177479.2(HDX):​c.1682C>T​(p.Pro561Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,180,010 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., 3 hem., cov: 22)
  • Exomes 𝑓: 0.000020 (0 hom. 8 hem.)
• Consequence: HDX NM_001177479.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61
• Publications: 1 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.073681).
• BS2: High Hemizygotes in GnomAd4 at 3 gene

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.1682C>T	p.Pro561Leu	missense	Exon 8 of 11	NP_001170950.1	Q7Z353-1
	HDX	NM_144657.5		c.1682C>T	p.Pro561Leu	missense	Exon 7 of 10	NP_653258.2
	HDX	NM_001177478.2		c.1508C>T	p.Pro503Leu	missense	Exon 7 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.1682C>T	p.Pro561Leu	missense	Exon 8 of 11	ENSP00000362272.2	Q7Z353-1
	HDX	ENST00000297977.9	TSL:1	c.1682C>T	p.Pro561Leu	missense	Exon 7 of 10	ENSP00000297977.5	Q7Z353-1
	HDX	ENST00000851225.1		c.1682C>T	p.Pro561Leu	missense	Exon 8 of 11	ENSP00000521284.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 8 AN: 110598 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000388

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: 0.0000570

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000542 AC: 9 AN: 166112 AF XY: 0.0000751

Gnomad AFR exome AF: 0.0000818

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000135

Gnomad OTH exome AF: 0.000248

GnomAD4 exome AF: 0.0000196 AC: 21 AN: 1069412 Hom.: 0 Cov.: 24 AF XY: 0.0000236 AC XY: 8 AN XY: 339030

African (AFR) AF: 0.0000390 AC: 1 AN: 25670

American (AMR) AF: 0.000357 AC: 12 AN: 33639

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18882

East Asian (EAS) AF: 0.00 AC: 0 AN: 29768

South Asian (SAS) AF: 0.0000393 AC: 2 AN: 50863

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39907

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4037

European-Non Finnish (NFE) AF: 0.00000609 AC: 5 AN: 821638

Other (OTH) AF: 0.0000222 AC: 1 AN: 45008

GnomAD4 genome AF: 0.0000723 AC: 8 AN: 110598 Hom.: 0 Cov.: 22 AF XY: 0.0000907 AC XY: 3 AN XY: 33062

African (AFR) AF: 0.0000328 AC: 1 AN: 30513

American (AMR) AF: 0.000388 AC: 4 AN: 10319

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2614

East Asian (EAS) AF: 0.00 AC: 0 AN: 3507

South Asian (SAS) AF: 0.00 AC: 0 AN: 2651

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5937

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000570 AC: 3 AN: 52661

Other (OTH) AF: 0.00 AC: 0 AN: 1476

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000413 AC: 5

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	0.072
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.9
DANN	Benign	0.85
DEOGEN2	Benign	0.056	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.6
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.034
Sift	Benign	0.22	T
Sift4G	Benign	0.33	T
Polyphen		0.0020	B
Vest4		0.078
MutPred		0.19		Loss of loop (P = 0.0128)
MVP		0.082
MPC		0.12
ClinPred		0.33	T
GERP RS		4.5
Varity_R		0.035
gMVP		0.12
Mutation Taster		=99/1	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: rs762465994; hg19: chrX-83591867; COSMIC: COSV52974085;