NM_001177479.2:c.1948G>A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001177479.2(HDX):​c.1948G>A​(p.Ala650Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000389 in 1,029,304 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000039 (0 hom. 0 hem.)
• Consequence: HDX NM_001177479.2 missense, splice_region
• Scores: Splicing: ADA: 0.9633
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>A	p.Ala650Thr	missense splice_region	Exon 11 of 11	NP_001170950.1	Q7Z353-1
	HDX	NM_144657.5		c.1948G>A	p.Ala650Thr	missense splice_region	Exon 10 of 10	NP_653258.2
	HDX	NM_001177478.2		c.1774G>A	p.Ala592Thr	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>A	p.Ala650Thr	missense splice_region	Exon 11 of 11	ENSP00000362272.2	Q7Z353-1
	HDX	ENST00000297977.9	TSL:1	c.1948G>A	p.Ala650Thr	missense splice_region	Exon 10 of 10	ENSP00000297977.5	Q7Z353-1
	HDX	ENST00000851225.1		c.1948G>A	p.Ala650Thr	missense splice_region	Exon 11 of 11	ENSP00000521284.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000389 AC: 4 AN: 1029304 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 310588

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

American (AMR) AF: 0.00 AC: 0 AN: 29488

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

East Asian (EAS) AF: 0.0000351 AC: 1 AN: 28459

South Asian (SAS) AF: 0.00 AC: 0 AN: 44975

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: 0.00000250 AC: 2 AN: 798842

Other (OTH) AF: 0.0000232 AC: 1 AN: 43135

GnomAD4 genome Cov.: 22

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	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.16
Sift	Benign	0.15	T
Sift4G	Benign	0.32	T
Polyphen		0.97	D
Vest4		0.31
MutPred		0.10		Gain of methylation at K645 (P = 0.0692)
MVP		0.42
MPC		0.13
ClinPred		0.74	D
GERP RS		5.5
Varity_R		0.069
gMVP		0.12
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Benign	0.70
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.32		Position offset: 0

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

Other links and lift over

dbSNP: rs1430032313; hg19: chrX-83577022;