1-160091938-G-A

Position:

• chr1-160091938-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_052868.6(IGSF8):​c.1727C>T​(p.Ala576Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IGSF8 NM_052868.6 missense, splice_region
• Scores: Splicing: ADA: 0.01026
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58

Genes affected

IGSF8 (HGNC:17813): (immunoglobulin superfamily member 8) This gene encodes a member the EWI subfamily of the immunoglobulin protein superfamily. Members of this family contain a single transmembrane domain, an EWI (Glu-Trp-Ile)-motif and a variable number of immunoglobulin domains. This protein interacts with the tetraspanins CD81 and CD9 and may regulate their role in certain cellular functions including cell migration and viral infection. The encoded protein may also function as a tumor suppressor by inhibiting the proliferation of certain cancers. Alternate splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27507064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGSF8	NM_052868.6	c.1727C>T	p.Ala576Val	missense_variant, splice_region_variant	6/7	ENST00000314485.12	NP_443100.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGSF8	ENST00000314485.12	c.1727C>T	p.Ala576Val	missense_variant, splice_region_variant	6/7	1	NM_052868.6	ENSP00000316664.7
IGSF8	ENST00000368086.5	c.1727C>T	p.Ala576Val	missense_variant, splice_region_variant	6/7	1		ENSP00000357065.1
IGSF8	ENST00000614243.4	c.1727C>T	p.Ala576Val	missense_variant, splice_region_variant	7/8	1		ENSP00000477565.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.1727C>T (p.A576V) alteration is located in exon 6 (coding exon 6) of the IGSF8 gene. This alteration results from a C to T substitution at nucleotide position 1727, causing the alanine (A) at amino acid position 576 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.051	T;T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.80	.;.;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.3	L;L;L
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.43	N;N;.
REVEL	Benign	0.078
Sift	Benign	0.27	T;T;.
Sift4G	Benign	0.14	T;T;T
Polyphen		0.077	B;B;B
Vest4		0.54
MutPred		0.56		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP		0.15
MPC		0.28
ClinPred		0.37	T
GERP RS		3.3
Varity_R		0.036
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.010
dbscSNV1_RF	Benign	0.21
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1649984246; hg19: chr1-160061728;