rs6529473

Variant names:

• chrX-131274771-G-A
• rs6529473
• NM_001555.5:c.3579C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-131274771-G-A
• chrX-131274771-G-C
• chrX-131274771-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001555.5(IGSF1):​c.3579C>T​(p.Val1193Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 1,208,393 control chromosomes in the GnomAD database, including 34,544 homozygotes. There are 107,036 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (4060 hom., 10057 hem., cov: 22)
  • Exomes 𝑓: 0.26 (30484 hom. 96979 hem.)
• Consequence: IGSF1 NM_001555.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.731
• Publications: 10 publications found

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)

ENSG00000287806 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant X-131274771-G-A is Benign according to our data. Variant chrX-131274771-G-A is described in ClinVar as Benign. ClinVar VariationId is 257592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.795 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGSF1	NM_001555.5	c.3579C>T	p.Val1193Val	synonymous_variant	Exon 18 of 20	ENST00000361420.8	NP_001546.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGSF1	ENST00000361420.8	c.3579C>T	p.Val1193Val	synonymous_variant	Exon 18 of 20	1	NM_001555.5	ENSP00000355010.3

Frequencies

GnomAD3 genomes AF: 0.299 AC: 33026 AN: 110535 Hom.: 4064 Cov.: 22

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.820

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.313

GnomAD2 exomes AF: 0.350 AC: 64209 AN: 183457 AF XY: 0.337

Gnomad AFR exome AF: 0.350

Gnomad AMR exome AF: 0.527

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.827

Gnomad FIN exome AF: 0.243

Gnomad NFE exome AF: 0.223

Gnomad OTH exome AF: 0.309

GnomAD4 exome AF: 0.263 AC: 289224 AN: 1097802 Hom.: 30484 Cov.: 33 AF XY: 0.267 AC XY: 96979 AN XY: 363248

African (AFR) AF: 0.355 AC: 9371 AN: 26395

American (AMR) AF: 0.517 AC: 18212 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 5007 AN: 19385

East Asian (EAS) AF: 0.816 AC: 24647 AN: 30203

South Asian (SAS) AF: 0.421 AC: 22803 AN: 54139

European-Finnish (FIN) AF: 0.239 AC: 9694 AN: 40524

Middle Eastern (MID) AF: 0.234 AC: 968 AN: 4137

European-Non Finnish (NFE) AF: 0.220 AC: 184846 AN: 841730

Other (OTH) AF: 0.297 AC: 13676 AN: 46087

GnomAD4 genome AF: 0.299 AC: 33037 AN: 110591 Hom.: 4060 Cov.: 22 AF XY: 0.306 AC XY: 10057 AN XY: 32879

African (AFR) AF: 0.345 AC: 10458 AN: 30330

American (AMR) AF: 0.415 AC: 4337 AN: 10444

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 659 AN: 2640

East Asian (EAS) AF: 0.821 AC: 2850 AN: 3473

South Asian (SAS) AF: 0.443 AC: 1142 AN: 2577

European-Finnish (FIN) AF: 0.235 AC: 1392 AN: 5916

Middle Eastern (MID) AF: 0.244 AC: 53 AN: 217

European-Non Finnish (NFE) AF: 0.219 AC: 11578 AN: 52807

Other (OTH) AF: 0.315 AC: 475 AN: 1510

Alfa AF: 0.260 Hom.: 20332

Bravo AF: 0.323

EpiCase AF: 0.222

EpiControl AF: 0.225

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

X-linked central congenital hypothyroidism with late-onset testicular enlargement Benign:1

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	-0.57
CADD	Benign	14
DANN	Benign	0.63
PhyloP100		0.73
PromoterAI		0.0044	Neutral
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.31		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6529473; hg19: chrX-130408745; COSMIC: COSV63838020; COSMIC: COSV63838020;