chrX-84322014-C-A

Variant names:

• chrX-84322014-C-A
• rs1430032313
• NM_001177479.2:c.1948G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001177479.2(HDX):​c.1948G>T​(p.Ala650Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A650T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: HDX NM_001177479.2 missense, splice_region
• Scores: Splicing: ADA: 0.9991
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.69
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.1948G>T	p.Ala650Ser	missense splice_region	Exon 11 of 11	NP_001170950.1	Q7Z353-1
	HDX	NM_144657.5		c.1948G>T	p.Ala650Ser	missense splice_region	Exon 10 of 10	NP_653258.2
	HDX	NM_001177478.2		c.1774G>T	p.Ala592Ser	missense splice_region	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.1948G>T	p.Ala650Ser	missense splice_region	Exon 11 of 11	ENSP00000362272.2	Q7Z353-1
	HDX	ENST00000297977.9	TSL:1	c.1948G>T	p.Ala650Ser	missense splice_region	Exon 10 of 10	ENSP00000297977.5	Q7Z353-1
	HDX	ENST00000851225.1		c.1948G>T	p.Ala650Ser	missense splice_region	Exon 11 of 11	ENSP00000521284.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1029301 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 310587

African (AFR) AF: 0.00 AC: 0 AN: 23853

American (AMR) AF: 0.00 AC: 0 AN: 29486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17576

East Asian (EAS) AF: 0.00 AC: 0 AN: 28459

South Asian (SAS) AF: 0.00 AC: 0 AN: 44973

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39097

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3879

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 798843

Other (OTH) AF: 0.00 AC: 0 AN: 43135

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
PhyloP100		3.7
Varity_R		0.066
gMVP		0.098
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.77		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1430032313; hg19: chrX-83577022;