NM_001555.5:c.3868C>G

Variant names:

• chrX-131274090-G-C
• rs749977306
• NM_001555.5:c.3868C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001555.5(IGSF1):​c.3868C>G​(p.Arg1290Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,209,308 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: IGSF1 NM_001555.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.29
• Publications: 1 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: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000287806 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGSF1	NM_001555.5	MANE Select	c.3868C>G	p.Arg1290Gly	missense	Exon 19 of 20	NP_001546.2
	IGSF1	NM_001170961.2		c.3883C>G	p.Arg1295Gly	missense	Exon 19 of 20	NP_001164432.1	Q8N6C5-4
	IGSF1	NM_001438811.1		c.3883C>G	p.Arg1295Gly	missense	Exon 20 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.3868C>G	p.Arg1290Gly	missense	Exon 19 of 20	ENSP00000355010.3	Q8N6C5-1
	IGSF1	ENST00000370903.8	TSL:1	c.3883C>G	p.Arg1295Gly	missense	Exon 19 of 20	ENSP00000359940.3	Q8N6C5-4
	IGSF1	ENST00000370910.5	TSL:1	c.3841C>G	p.Arg1281Gly	missense	Exon 18 of 19	ENSP00000359947.1	Q8N6C5-2

Frequencies

GnomAD3 genomes AF: 0.00000898 AC: 1 AN: 111366 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

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: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097942 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363304

African (AFR) AF: 0.00 AC: 0 AN: 26394

American (AMR) AF: 0.00 AC: 0 AN: 35184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19373

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00 AC: 0 AN: 54118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841936

Other (OTH) AF: 0.00 AC: 0 AN: 46088

GnomAD4 genome AF: 0.00000898 AC: 1 AN: 111366 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33560

African (AFR) AF: 0.00 AC: 0 AN: 30582

American (AMR) AF: 0.00 AC: 0 AN: 10510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3536

South Asian (SAS) AF: 0.00 AC: 0 AN: 2614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6047

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 53021

Other (OTH) AF: 0.00 AC: 0 AN: 1493

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.3
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.15
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.39	B
Vest4		0.65
MutPred		0.61		Loss of MoRF binding (P = 0.0622)
MVP		0.13
MPC		0.62
ClinPred		0.75	D
GERP RS		4.5
Varity_R		0.23
gMVP		0.51
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs749977306; hg19: chrX-130408064;