chrX-131281844-T-C

Variant names:

• chrX-131281844-T-C
• rs1128617
• NM_001555.5:c.1347A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001170961.2(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_001170961.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.225
• Publications: 12 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 -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001170961.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGSF1	NM_001555.5	MANE Select	c.1347A>G	p.Glu449Glu	synonymous	Exon 8 of 20	NP_001546.2
	IGSF1	NM_001170961.2		c.1347A>G	p.Glu449Glu	synonymous	Exon 8 of 20	NP_001164432.1
	IGSF1	NM_001438811.1		c.1347A>G	p.Glu449Glu	synonymous	Exon 9 of 21	NP_001425740.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGSF1	ENST00000361420.8	TSL:1 MANE Select	c.1347A>G	p.Glu449Glu	synonymous	Exon 8 of 20	ENSP00000355010.3
	IGSF1	ENST00000370903.8	TSL:1	c.1347A>G	p.Glu449Glu	synonymous	Exon 8 of 20	ENSP00000359940.3
	IGSF1	ENST00000370910.5	TSL:1	c.1320A>G	p.Glu440Glu	synonymous	Exon 7 of 19	ENSP00000359947.1

Frequencies

GnomAD3 genomes AF: 0.481 AC: 52783 AN: 109839 Hom.: 9226 Cov.: 22

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

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.: 33 AF XY: 0.450 AC XY: 163186 AN XY: 362330

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

GnomAD4 genome AF: 0.481 AC: 52819 AN: 109896 Hom.: 9229 Cov.: 22 AF XY: 0.472 AC XY: 15226 AN XY: 32234

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: 90 AN: 213

European-Non Finnish (NFE) AF: 0.446 AC: 23465 AN: 52658

Other (OTH) AF: 0.483 AC: 722 AN: 1494

Alfa AF: 0.454 Hom.: 41934

Bravo AF: 0.488

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	X-linked central congenital hypothyroidism with late-onset testicular enlargement (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.0
DANN	Benign	0.70
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1128617; hg19: chrX-130415818; COSMIC: COSV63836489; COSMIC: COSV63836489;