X-131274799-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001555.5(IGSF1):c.3551G>A(p.Arg1184Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000908 in 1,209,760 control chromosomes in the GnomAD database, including 6 homozygotes. There are 330 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00079 (1 hom., 24 hem., cov: 23)
  • Exomes 𝑓: 0.00092 (5 hom. 306 hem.)
• Consequence: IGSF1 NM_001555.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.668

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076056123).
• BP6: Variant X-131274799-C-T is Benign according to our data. Variant chrX-131274799-C-T is described in ClinVar as [Benign]. Clinvar id is 3039420.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000795 (89/111997) while in subpopulation EAS AF= 0.00957 (34/3551). AF 95% confidence interval is 0.00704. There are 1 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGSF1	NM_001555.5	c.3551G>A	p.Arg1184Gln	missense_variant	18/20	ENST00000361420.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGSF1	ENST00000361420.8	c.3551G>A	p.Arg1184Gln	missense_variant	18/20	1	NM_001555.5	P4

Frequencies

GnomAD3 genomes AF: 0.000795 AC: 89 AN: 111943 Hom.: 1 Cov.: 23 AF XY: 0.000704 AC XY: 24 AN XY: 34109

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000754

Gnomad EAS AF: 0.00955

Gnomad SAS AF: 0.000753

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000884

Gnomad OTH AF: 0.00198

GnomAD3 exomes AF: 0.00123 AC: 225 AN: 183484 Hom.: 2 AF XY: 0.00113 AC XY: 77 AN XY: 67918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000438

Gnomad ASJ exome AF: 0.000534

Gnomad EAS exome AF: 0.0105

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000647

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.000920 AC: 1010 AN: 1097763 Hom.: 5 Cov.: 32 AF XY: 0.000843 AC XY: 306 AN XY: 363119

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000369

Gnomad4 ASJ exome AF: 0.000464

Gnomad4 EAS exome AF: 0.0176

Gnomad4 SAS exome AF: 0.000369

Gnomad4 FIN exome AF: 0.0000493

Gnomad4 NFE exome AF: 0.000469

Gnomad4 OTH exome AF: 0.000781

GnomAD4 genome AF: 0.000795 AC: 89 AN: 111997 Hom.: 1 Cov.: 23 AF XY: 0.000702 AC XY: 24 AN XY: 34173

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000754

Gnomad4 EAS AF: 0.00957

Gnomad4 SAS AF: 0.000756

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000884

Gnomad4 OTH AF: 0.00196

Alfa AF: 0.00139 Hom.: 57

Bravo AF: 0.000646

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000743 AC: 5

ExAC AF: 0.00121 AC: 147

EpiCase AF: 0.000545

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

IGSF1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 16, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	23
Dann	Uncertain	1.0
FATHMM_MKL	Benign	0.66	D
MetaRNN	Benign	0.0076	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.95	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.060	N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.33	T;T;T;T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		1.0	D;D;.;D
Vest4		0.32
MVP		0.19
MPC		0.80
ClinPred		0.044	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs146525641; hg19: chrX-130408773; COSMIC: COSV63837682; COSMIC: COSV63837682;