Genetic Variant HSFX3:p.Ile310Ile (chrX-149548464-G-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP7BS2

The NM_001323079.3(HSFX3):c.930C>A(p.Ile310Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000311 in 931,163 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I310I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 1 hem., cov: 19)

Exomes 𝑓: 0.000029 ( 0 hom. 8 hem. )

Consequence

HSFX3
NM_001323079.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.479

Publications

0 publications found

Variant links:

Genes affected

HSFX3 (HGNC:52395): (heat shock transcription factor family, X-linked member 3) 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 part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

HSFX3 links:

EOLA1 (HGNC:28089): (endothelium and lymphocyte associated ASCH domain 1) Involved in regulation of interleukin-6 production. [provided by Alliance of Genome Resources, Apr 2022]

EOLA1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP7

Synonymous conserved (PhyloP=-0.479 with no splicing effect.

BS2

High Hemizygotes in GnomAdExome4 at 8 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323079.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSFX3	NM_001323079.3	MANE Select	c.930C>A	p.Ile310Ile	synonymous	Exon 2 of 2	NP_001310008.1	A0A1B0GWH4
EOLA1	NM_001171909.4		c.433-952G>T		intron	N/A	NP_001165380.1	Q8TE69-2
EOLA1	NM_001324276.2		c.433-952G>T		intron	N/A	NP_001311205.1	Q8TE69-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSFX3	ENST00000431993.4	TSL:3 MANE Select	c.930C>A	p.Ile310Ile	synonymous	Exon 2 of 2	ENSP00000490928.1	A0A1B0GWH4
EOLA1	ENST00000422892.2	TSL:2	c.433-952G>T		intron	N/A	ENSP00000422312.1	Q8TE69-2
EOLA1	ENST00000434353.6	TSL:5	c.433-952G>T		intron	N/A	ENSP00000423160.1	Q8TE69-2

Frequencies

GnomAD3 genomes

AF:

0.0000452

AC:

AN:

110532

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000953

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00858

Gnomad NFE

AF:

0.0000379

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000292

AC:

AN:

820574

Hom.:

Cov.:

AF XY:

0.0000319

AC XY:

AN XY:

250692

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17888

American (AMR)

AF:

0.00

AC:

AN:

6444

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10431

East Asian (EAS)

AF:

0.00

AC:

AN:

20389

South Asian (SAS)

AF:

0.00

AC:

AN:

14153

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16403

Middle Eastern (MID)

AF:

0.000498

AC:

AN:

2010

European-Non Finnish (NFE)

AF:

0.0000286

AC:

AN:

699284

Other (OTH)

AF:

0.0000894

AC:

AN:

33572

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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

AF:

0.0000452

AC:

AN:

110589

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

32991

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30216

American (AMR)

AF:

0.0000952

AC:

AN:

10508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2579

East Asian (EAS)

AF:

0.00

AC:

AN:

3549

South Asian (SAS)

AF:

0.00

AC:

AN:

2589

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5995

Middle Eastern (MID)

AF:

0.00935

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.0000379

AC:

AN:

52770

Other (OTH)

AF:

0.00

AC:

AN:

1489

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.000108

Hom.:

Bravo

AF:

0.0000340

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.33

(source)

DANN

Benign

0.52

PhyloP100

-0.48

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