rs397514622

Variant names:

• chrX-131276974-G-A
• rs397514622
• NM_001555.5:c.2573C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-131276974-G-A
• chrX-131276974-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001555.5(IGSF1):​c.2573C>T​(p.Ser858Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: IGSF1 NM_001555.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.08
• Publications: 7 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ENSG00000287806 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863
• PP5: Variant X-131276974-G-A is Pathogenic according to our data. Variant chrX-131276974-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 39852.Status of the report is no_assertion_criteria_provided, 0 stars.

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.2573C>T	p.Ser858Phe	missense	Exon 14 of 20	NP_001546.2
	IGSF1	NM_001170961.2		c.2588C>T	p.Ser863Phe	missense	Exon 14 of 20	NP_001164432.1	Q8N6C5-4
	IGSF1	NM_001438811.1		c.2588C>T	p.Ser863Phe	missense	Exon 15 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.2573C>T	p.Ser858Phe	missense	Exon 14 of 20	ENSP00000355010.3	Q8N6C5-1
	IGSF1	ENST00000370903.8	TSL:1	c.2588C>T	p.Ser863Phe	missense	Exon 14 of 20	ENSP00000359940.3	Q8N6C5-4
	IGSF1	ENST00000370910.5	TSL:1	c.2546C>T	p.Ser849Phe	missense	Exon 13 of 19	ENSP00000359947.1	Q8N6C5-2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	X-linked central congenital hypothyroidism with late-onset testicular enlargement (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.86	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Pathogenic	4.3	H
PhyloP100		5.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.55		Loss of disorder (P = 0.0104)
MVP		0.66
MPC		0.78
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.98
gMVP		0.79
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs397514622; hg19: chrX-130410948;