NM_001555.5:c.1347A>C

Variant names:

• chrX-131281844-T-G
• rs1128617
• NM_001555.5:c.1347A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001555.5(IGSF1):​c.1347A>C​(p.Glu449Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E449E) has been classified as Benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: IGSF1 NM_001555.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.225
• Publications: 12 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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000287806 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14442232).

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.1347A>C	p.Glu449Asp	missense	Exon 8 of 20	NP_001546.2
	IGSF1	NM_001170961.2		c.1347A>C	p.Glu449Asp	missense	Exon 8 of 20	NP_001164432.1
	IGSF1	NM_001438811.1		c.1347A>C	p.Glu449Asp	missense	Exon 9 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.1347A>C	p.Glu449Asp	missense	Exon 8 of 20	ENSP00000355010.3
	IGSF1	ENST00000370903.8	TSL:1	c.1347A>C	p.Glu449Asp	missense	Exon 8 of 20	ENSP00000359940.3
	IGSF1	ENST00000370910.5	TSL:1	c.1320A>C	p.Glu440Asp	missense	Exon 7 of 19	ENSP00000359947.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.23
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.13
Sift	Benign	0.20	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.10
MutPred		0.28		Loss of sheet (P = 0.1158)
MVP		0.23
MPC		0.71
ClinPred		0.84	D
GERP RS		3.2
Varity_R		0.13
gMVP		0.24
Mutation Taster		=93/7	polymorphism

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: rs1128617; hg19: chrX-130415818;