rs4830219

chrX-131276991-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001555.5(IGSF1):c.2556T>C(p.Tyr852=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0130

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 257591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-131276991-A-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
IGSF1	NM_001555.5	c.2556T>C	p.Tyr852=	synonymous_variant	14/20	ENST00000361420.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGSF1	ENST00000361420.8	c.2556T>C	p.Tyr852=	synonymous_variant	14/20	1	NM_001555.5	P4

Frequencies

GnomAD3 genomes AF: 0.351 AC: 38727 AN: 110427 Hom.: 5257 Cov.: 22 AF XY: 0.331 AC XY: 10833 AN XY: 32693

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

GnomAD3 exomes AF: 0.297 AC: 54468 AN: 183220 Hom.: 6066 AF XY: 0.289 AC XY: 19589 AN XY: 67694

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 SAS exome AF: 0.146

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.: 32 AF XY: 0.318 AC XY: 115378 AN XY: 363264

Gnomad4 AFR exome AF: 0.430

Gnomad4 AMR exome AF: 0.303

Gnomad4 ASJ exome AF: 0.361

Gnomad4 EAS exome AF: 0.00238

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.345

Gnomad4 NFE exome AF: 0.343

Gnomad4 OTH exome AF: 0.315

GnomAD4 genome AF: 0.351 AC: 38767 AN: 110480 Hom.: 5265 Cov.: 22 AF XY: 0.331 AC XY: 10858 AN XY: 32756

Gnomad4 AFR AF: 0.426

Gnomad4 AMR AF: 0.340

Gnomad4 ASJ AF: 0.340

Gnomad4 EAS AF: 0.00283

Gnomad4 SAS AF: 0.123

Gnomad4 FIN AF: 0.321

Gnomad4 NFE AF: 0.348

Gnomad4 OTH AF: 0.347

Alfa AF: 0.342 Hom.: 21428

Bravo AF: 0.358

EpiCase AF: 0.347

EpiControl AF: 0.346

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

X-linked central congenital hypothyroidism with late-onset testicular enlargement Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	4.9
Dann	Benign	0.24

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

LitVar

Other links and lift over

dbSNP: rs4830219; hg19: chrX-130410965; COSMIC: COSV63836051; COSMIC: COSV63836051;