dbSNP rs149959109: IGSF1:p.Glu1282Asp (chrX-131274112-C-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001555.5(IGSF1):c.3846G>C(p.Glu1282Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,209,788 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 43 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., 10 hem., cov: 23)

Exomes 𝑓: 0.00011 ( 0 hom. 33 hem. )

Consequence

IGSF1
NM_001555.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0410

Publications

0 publications found

Variant links:

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: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

IGSF1 links:

ENSG00000287806 (HGNC:):

ENSG00000287806 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014509708).

BP6

Variant X-131274112-C-G is Benign according to our data. Variant chrX-131274112-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3108783.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000107 (117/1098122) while in subpopulation NFE AF = 0.000133 (112/842024). AF 95% confidence interval is 0.000113. There are 0 homozygotes in GnomAdExome4. There are 33 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 10 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001555.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IGSF1	NM_001555.5	MANE Select	c.3846G>C	p.Glu1282Asp	missense	Exon 19 of 20	NP_001546.2
IGSF1	NM_001170961.2		c.3861G>C	p.Glu1287Asp	missense	Exon 19 of 20	NP_001164432.1	Q8N6C5-4
IGSF1	NM_001438811.1		c.3861G>C	p.Glu1287Asp	missense	Exon 20 of 21	NP_001425740.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IGSF1	ENST00000361420.8	TSL:1 MANE Select	c.3846G>C	p.Glu1282Asp	missense	Exon 19 of 20	ENSP00000355010.3	Q8N6C5-1
IGSF1	ENST00000370903.8	TSL:1	c.3861G>C	p.Glu1287Asp	missense	Exon 19 of 20	ENSP00000359940.3	Q8N6C5-4
IGSF1	ENST00000370910.5	TSL:1	c.3819G>C	p.Glu1273Asp	missense	Exon 18 of 19	ENSP00000359947.1	Q8N6C5-2

Frequencies

GnomAD3 genomes

AF:

0.000260

AC:

AN:

111666

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.0379

Gnomad AMR

AF:

0.00

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:

0.0000565

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000273

AC:

AN:

183366

AF XY:

0.0000590

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000611

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000107

AC:

117

AN:

1098122

Hom.:

Cov.:

AF XY:

0.0000908

AC XY:

AN XY:

363478

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26401

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.000133

AC:

112

AN:

842024

Other (OTH)

AF:

0.0000868

AC:

AN:

46095

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000260

AC:

AN:

111666

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

33814

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30684

American (AMR)

AF:

0.00

AC:

AN:

10572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3536

South Asian (SAS)

AF:

0.00

AC:

AN:

2629

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6078

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000565

AC:

AN:

53099

Other (OTH)

AF:

0.00

AC:

AN:

1497

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000412

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.045

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.78

M_CAP

Benign

0.015

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.81

PhyloP100

-0.041

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.0

REVEL

Benign

0.21

Sift

Benign

0.066

Sift4G

Benign

0.13

Polyphen

0.55

Vest4

0.59

MutPred

0.49

Loss of sheet (P = 0.0126)

MVP

0.12

MPC

0.71

ClinPred

0.22

GERP RS

0.80

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.39

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over