X-131281844-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001555.5(IGSF1):c.1347A>G(p.Glu449Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 1,206,628 control chromosomes in the GnomAD database, including 86,860 homozygotes. There are 178,412 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 9229 hom., 15226 hem., cov: 22)

Exomes 𝑓: 0.45 ( 77631 hom. 163186 hem. )

Consequence

IGSF1
NM_001555.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.225

Publications

12 publications found

Variant links:

Genes affected

IGSF1 (HGNC:5948): (immunoglobulin superfamily member 1) This gene encodes a member of the immunoglobulin-like domain-containing superfamily. Proteins in this superfamily contain varying numbers of immunoglobulin-like domains and are thought to participate in the regulation of interactions between cells. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]

IGSF1 Gene-Disease associations (from GenCC):

X-linked central congenital hypothyroidism with late-onset testicular enlargement
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

IGSF1 links:

ENSG00000287806 (HGNC:):

ENSG00000287806 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant X-131281844-T-C is Benign according to our data. Variant chrX-131281844-T-C is described in ClinVar as Benign. ClinVar VariationId is 257590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.225 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGSF1	NM_001555.5 link	c.1347A>G	p.Glu449Glu	synonymous_variant	Exon 8 of 20	ENST00000361420.8	NP_001546.2	Q8N6C5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGSF1	ENST00000361420.8 link	c.1347A>G	p.Glu449Glu	synonymous_variant	Exon 8 of 20	1	NM_001555.5	ENSP00000355010.3		Q8N6C5-1

Frequencies

GnomAD3 genomes

AF:

0.481

AC:

52783

AN:

109839

Hom.:

9226

Cov.:

show subpopulations

Gnomad AFR

AF:

0.537

Gnomad AMI

AF:

0.468

Gnomad AMR

AF:

0.463

Gnomad ASJ

AF:

0.470

Gnomad EAS

AF:

0.665

Gnomad SAS

AF:

0.350

Gnomad FIN

AF:

0.495

Gnomad MID

AF:

0.427

Gnomad NFE

AF:

0.446

Gnomad OTH

AF:

0.485

GnomAD2 exomes

AF:

0.467

AC:

85349

AN:

182704

AF XY:

0.459

show subpopulations

Gnomad AFR exome

AF:

0.537

Gnomad AMR exome

AF:

0.431

Gnomad ASJ exome

AF:

0.470

Gnomad EAS exome

AF:

0.681

Gnomad FIN exome

AF:

0.506

Gnomad NFE exome

AF:

0.448

Gnomad OTH exome

AF:

0.441

GnomAD4 exome

AF:

0.454

AC:

498210

AN:

1096732

Hom.:

77631

Cov.:

AF XY:

0.450

AC XY:

163186

AN XY:

362330

show subpopulations

African (AFR)

AF:

0.545

AC:

14384

AN:

26376

American (AMR)

AF:

0.436

AC:

15326

AN:

35163

Ashkenazi Jewish (ASJ)

AF:

0.467

AC:

9050

AN:

19378

East Asian (EAS)

AF:

0.691

AC:

20855

AN:

30194

South Asian (SAS)

AF:

0.376

AC:

20334

AN:

54115

European-Finnish (FIN)

AF:

0.499

AC:

20206

AN:

40478

Middle Eastern (MID)

AF:

0.436

AC:

1800

AN:

4133

European-Non Finnish (NFE)

AF:

0.446

AC:

375023

AN:

840841

Other (OTH)

AF:

0.461

AC:

21232

AN:

46054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

10066

20132

30199

40265

50331

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12520

25040

37560

50080

62600

<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:

0.481

AC:

52819

AN:

109896

Hom.:

9229

Cov.:

AF XY:

0.472

AC XY:

15226

AN XY:

32234

show subpopulations

African (AFR)

AF:

0.536

AC:

16168

AN:

30138

American (AMR)

AF:

0.463

AC:

4790

AN:

10339

Ashkenazi Jewish (ASJ)

AF:

0.470

AC:

1238

AN:

2635

East Asian (EAS)

AF:

0.666

AC:

2295

AN:

3446

South Asian (SAS)

AF:

0.350

AC:

902

AN:

2578

European-Finnish (FIN)

AF:

0.495

AC:

2838

AN:

5731

Middle Eastern (MID)

AF:

0.423

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.446

AC:

23465

AN:

52658

Other (OTH)

AF:

0.483

AC:

722

AN:

1494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

984

1968

2953

3937

4921

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

484

968

1452

1936

2420

<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:

0.454

Hom.:

41934

Bravo

AF:

0.488

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

X-linked central congenital hypothyroidism with late-onset testicular enlargement

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

8.0

(source)

DANN

Benign

0.70

PhyloP100

0.23

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over