X-131275095-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001555.5(IGSF1):c.3376G>A(p.Gly1126Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000881 in 1,209,191 control chromosomes in the GnomAD database, including 6 homozygotes. There are 275 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (4 hom., 149 hem., cov: 23)
  • Exomes 𝑓: 0.00048 (2 hom. 126 hem.)
• Consequence: IGSF1 NM_001555.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.522

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029359162).
• BP6: Variant X-131275095-C-T is Benign according to our data. Variant chrX-131275095-C-T is described in ClinVar as [Benign]. Clinvar id is 777841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00477 (533/111835) while in subpopulation AFR AF= 0.0162 (498/30778). AF 95% confidence interval is 0.015. There are 4 homozygotes in gnomad4. There are 149 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGSF1	NM_001555.5	c.3376G>A	p.Gly1126Ser	missense_variant	17/20	ENST00000361420.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGSF1	ENST00000361420.8	c.3376G>A	p.Gly1126Ser	missense_variant	17/20	1	NM_001555.5	P4

Frequencies

GnomAD3 genomes AF: 0.00477 AC: 533 AN: 111781 Hom.: 4 Cov.: 23 AF XY: 0.00436 AC XY: 148 AN XY: 33941

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00245

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00530

GnomAD3 exomes AF: 0.00148 AC: 271 AN: 183464 Hom.: 2 AF XY: 0.00100 AC XY: 68 AN XY: 67898

Gnomad AFR exome AF: 0.0176

Gnomad AMR exome AF: 0.00109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000244

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000485 AC: 532 AN: 1097356 Hom.: 2 Cov.: 32 AF XY: 0.000347 AC XY: 126 AN XY: 362718

Gnomad4 AFR exome AF: 0.0165

Gnomad4 AMR exome AF: 0.00102

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000832

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.00477 AC: 533 AN: 111835 Hom.: 4 Cov.: 23 AF XY: 0.00438 AC XY: 149 AN XY: 34005

Gnomad4 AFR AF: 0.0162

Gnomad4 AMR AF: 0.00245

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00524

Alfa AF: 0.000418 Hom.: 20

Bravo AF: 0.00537

ESP6500AA AF: 0.0141 AC: 54

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00166 AC: 201

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

IGSF1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.93	T
BayesDel_noAF	Benign	-1.1
Cadd	Benign	1.6
Dann	Benign	0.50
FATHMM_MKL	Benign	0.023	N
MetaRNN	Benign	0.0029	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.70	N;N;N;N
REVEL	Benign	0.040
Sift	Benign	0.48	T;T;T;T
Sift4G	Benign	0.51	T;T;T;T
Polyphen		0.0	B;B;.;B
Vest4		0.051
MVP		0.068
MPC		0.19
ClinPred		0.0011	T
GERP RS		-0.46
Varity_R		0.043
gMVP		0.33

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

LitVar

Other links and lift over

dbSNP: rs143211470; hg19: chrX-130409069;