NM_001555.5:c.3710G>C

Variant names:

• chrX-131274640-C-G
• rs2080454400
• NM_001555.5:c.3710G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001555.5(IGSF1):​c.3710G>C​(p.Trp1237Ser) 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 1,210,241 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: IGSF1 NM_001555.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.599
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796

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.3710G>C	p.Trp1237Ser	missense	Exon 18 of 20	NP_001546.2
	IGSF1	NM_001170961.2		c.3725G>C	p.Trp1242Ser	missense	Exon 18 of 20	NP_001164432.1	Q8N6C5-4
	IGSF1	NM_001438811.1		c.3725G>C	p.Trp1242Ser	missense	Exon 19 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.3710G>C	p.Trp1237Ser	missense	Exon 18 of 20	ENSP00000355010.3	Q8N6C5-1
	IGSF1	ENST00000370903.8	TSL:1	c.3725G>C	p.Trp1242Ser	missense	Exon 18 of 20	ENSP00000359940.3	Q8N6C5-4
	IGSF1	ENST00000370910.5	TSL:1	c.3683G>C	p.Trp1228Ser	missense	Exon 17 of 19	ENSP00000359947.1	Q8N6C5-2

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112309 Hom.: 0 Cov.: 24

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097932 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363290

African (AFR) AF: 0.00 AC: 0 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19371

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40521

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

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841900

Other (OTH) AF: 0.0000217 AC: 1 AN: 46084

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112309 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34475

African (AFR) AF: 0.00 AC: 0 AN: 30869

American (AMR) AF: 0.00 AC: 0 AN: 10707

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.00 AC: 0 AN: 2679

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6213

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53181

Other (OTH) AF: 0.00 AC: 0 AN: 1523

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	IGSF1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.60
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.60
MutPred		0.71		Gain of disorder (P = 5e-04)
MVP		0.36
MPC		0.96
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.92
gMVP		0.81
Mutation Taster		=44/56	disease causing

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: rs2080454400; hg19: chrX-130408614;