Genetic Variant NM_001351114.2:c.939C>T (chrX-149931042-C-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_StrongBP6_ModerateBP7

The NM_001351114.2(HSFX4):c.939C>T(p.Tyr313Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., 29 hem., cov: 20)

Exomes 𝑓: 0.00026 ( 1 hom. 94 hem. )

Failed GnomAD Quality Control

Consequence

HSFX4
NM_001351114.2 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.23

Publications

0 publications found

Variant links:

Genes affected

HSFX4 (HGNC:52398): (heat shock transcription factor family, X-linked member 4) Predicted to enable DNA-binding transcription factor activity 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 active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

HSFX4 links:

EOLA2 (HGNC:17402): (endothelium and lymphocyte associated ASCH domain 2)

EOLA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BP6

Variant X-149931042-C-T is Benign according to our data. Variant chrX-149931042-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2661624.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.23 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001351114.2. 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
	HSFX4	NM_001351114.2	MANE Select	c.939C>T	p.Tyr313Tyr	synonymous	Exon 2 of 2	NP_001338043.1	A0A1B0GTS1
	EOLA2	NM_001437940.1		c.433-961G>A		intron	N/A	NP_001424869.1	Q5HY62

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSFX4	ENST00000457775.3	TSL:3 MANE Select	c.939C>T	p.Tyr313Tyr	synonymous	Exon 2 of 2	ENSP00000489814.2	A0A1B0GTS1
	EOLA2	ENST00000462691.5	TSL:3	c.433-961G>A		intron	N/A	ENSP00000417546.1	Q5HY62

Frequencies

GnomAD3 genomes

AF:

0.00227

AC:

253

AN:

111555

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00690

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000945

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000564

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.000490

Gnomad OTH

AF:

0.00267

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000265

AC:

218

AN:

824030

Hom.:

Cov.:

AF XY:

0.000369

AC XY:

AN XY:

254434

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00303

AC:

AN:

17843

American (AMR)

AF:

0.00140

AC:

AN:

6450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10656

East Asian (EAS)

AF:

0.00328

AC:

AN:

20404

South Asian (SAS)

AF:

0.000141

AC:

AN:

14139

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16496

Middle Eastern (MID)

AF:

0.000496

AC:

AN:

2016

European-Non Finnish (NFE)

AF:

0.000104

AC:

AN:

702339

Other (OTH)

AF:

0.000356

AC:

AN:

33687

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.265

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00227

AC:

253

AN:

111604

Hom.:

Cov.:

AF XY:

0.000856

AC XY:

AN XY:

33894

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00688

AC:

210

AN:

30516

American (AMR)

AF:

0.000944

AC:

AN:

10595

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.000565

AC:

AN:

3539

South Asian (SAS)

AF:

0.00

AC:

AN:

2680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6112

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000490

AC:

AN:

53095

Other (OTH)

AF:

0.00264

AC:

AN:

1517

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00159

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.24

(source)

DANN

Benign

0.54

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over