chrX-131276991-A-G

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.2556T>C(p.Tyr852Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 1,208,294 control chromosomes in the GnomAD database, including 46,618 homozygotes. There are 126,236 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 5265 hom., 10858 hem., cov: 22)

Exomes 𝑓: 0.32 ( 41353 hom. 115378 hem. )

Consequence

IGSF1
NM_001555.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0130

Publications

8 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=-0.64).

BP6

Variant X-131276991-A-G is Benign according to our data. Variant chrX-131276991-A-G is described in ClinVar as Benign. ClinVar VariationId is 257591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.013 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGSF1	NM_001555.5 link	c.2556T>C	p.Tyr852Tyr	synonymous_variant	Exon 14 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.2556T>C	p.Tyr852Tyr	synonymous_variant	Exon 14 of 20	1	NM_001555.5	ENSP00000355010.3		Q8N6C5-1

Frequencies

GnomAD3 genomes

AF:

0.351

AC:

38727

AN:

110427

Hom.:

5257

Cov.:

show subpopulations

Gnomad AFR

AF:

0.426

Gnomad AMI

AF:

0.365

Gnomad AMR

AF:

0.340

Gnomad ASJ

AF:

0.340

Gnomad EAS

AF:

0.00254

Gnomad SAS

AF:

0.123

Gnomad FIN

AF:

0.321

Gnomad MID

AF:

0.278

Gnomad NFE

AF:

0.348

Gnomad OTH

AF:

0.349

GnomAD2 exomes

AF:

0.297

AC:

54468

AN:

183220

AF XY:

0.289

show subpopulations

Gnomad AFR exome

AF:

0.429

Gnomad AMR exome

AF:

0.301

Gnomad ASJ exome

AF:

0.360

Gnomad EAS exome

AF:

0.00137

Gnomad FIN exome

AF:

0.344

Gnomad NFE exome

AF:

0.345

Gnomad OTH exome

AF:

0.311

GnomAD4 exome

AF:

0.325

AC:

356259

AN:

1097814

Hom.:

41353

Cov.:

AF XY:

0.318

AC XY:

115378

AN XY:

363264

show subpopulations

African (AFR)

AF:

0.430

AC:

11350

AN:

26395

American (AMR)

AF:

0.303

AC:

10665

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.361

AC:

7004

AN:

19382

East Asian (EAS)

AF:

0.00238

AC:

AN:

30205

South Asian (SAS)

AF:

0.156

AC:

8439

AN:

54141

European-Finnish (FIN)

AF:

0.345

AC:

14001

AN:

40525

Middle Eastern (MID)

AF:

0.320

AC:

1321

AN:

4132

European-Non Finnish (NFE)

AF:

0.343

AC:

288888

AN:

841751

Other (OTH)

AF:

0.315

AC:

14519

AN:

46080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

8674

17348

26023

34697

43371

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9830

19660

29490

39320

49150

<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:

0.351

AC:

38767

AN:

110480

Hom.:

5265

Cov.:

AF XY:

0.331

AC XY:

10858

AN XY:

32756

show subpopulations

African (AFR)

AF:

0.426

AC:

12883

AN:

30257

American (AMR)

AF:

0.340

AC:

3545

AN:

10412

Ashkenazi Jewish (ASJ)

AF:

0.340

AC:

893

AN:

2627

East Asian (EAS)

AF:

0.00283

AC:

AN:

3531

South Asian (SAS)

AF:

0.123

AC:

318

AN:

2580

European-Finnish (FIN)

AF:

0.321

AC:

1901

AN:

5913

Middle Eastern (MID)

AF:

0.280

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.348

AC:

18388

AN:

52766

Other (OTH)

AF:

0.347

AC:

523

AN:

1506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

903

1805

2708

3610

4513

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

366

732

1098

1464

1830

<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:

0.346

Hom.:

30351

Bravo

AF:

0.358

EpiCase

AF:

0.347

EpiControl

AF:

0.346

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

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

4.9

(source)

DANN

Benign

0.24

PhyloP100

0.013

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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