dbSNP rs1430032313: HDX:p.Ala650Ser (chrX-84322014-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

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

Variant links:

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]

HDX links:

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ACMG classification

Classification was made for transcript

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

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

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.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1029301

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

310587

African (AFR)

AF:

0.00

AC:

AN:

23853

American (AMR)

AF:

0.00

AC:

AN:

29486

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17576

East Asian (EAS)

AF:

0.00

AC:

AN:

28459

South Asian (SAS)

AF:

0.00

AC:

AN:

44973

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39097

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3879

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

798843

Other (OTH)

AF:

0.00

AC:

AN:

43135

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.40

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

3.7

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.47

REVEL

Benign

0.17

Sift

Benign

0.074

Sift4G

Benign

0.090

Polyphen

0.99

Vest4

0.30

MutPred

0.10

Gain of phosphorylation at A650 (P = 0.036)

MVP

0.40

MPC

0.14

ClinPred

0.81

GERP RS

5.5

Varity_R

0.066

gMVP

0.098

Mutation Taster

=80/20

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over