Genetic Variant SNED1:p.Ile211Met (chr2-241033866-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001080437.3(SNED1):c.633C>G(p.Ile211Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SNED1
NM_001080437.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.77

Variant links:

Genes affected

SNED1 (HGNC:24696): (sushi, nidogen and EGF like domains 1) Predicted to enable Notch binding activity. Predicted to be involved in cell-matrix adhesion. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

SNED1 links:

SNED1-AS1 (HGNC:41060): (SNED1 antisense RNA 1)

SNED1-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNED1	NM_001080437.3 link	c.633C>G	p.Ile211Met	missense_variant	Exon 3 of 32	ENST00000310397.13	NP_001073906.1	Q8TER0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SNED1	ENST00000310397.13 link	c.633C>G	p.Ile211Met	missense_variant	Exon 3 of 32	5	NM_001080437.3	ENSP00000308893.8	Q8TER0-1
SNED1	ENST00000405547.7 link	c.633C>G	p.Ile211Met	missense_variant	Exon 3 of 30	5		ENSP00000386007.3	Q8TER0-3
SNED1	ENST00000401884.5 link	c.633C>G	p.Ile211Met	missense_variant	Exon 3 of 27	5		ENSP00000384871.1	Q8TER0-5
SNED1-AS1	ENST00000458377.1 link	n.38-263G>C		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1450308

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720432

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.633C>G (p.I211M) alteration is located in exon 3 (coding exon 3) of the SNED1 gene. This alteration results from a C to G substitution at nucleotide position 633, causing the isoleucine (I) at amino acid position 211 to be replaced by a methionine (M). 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

0.32

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Benign

-0.29

CADD

Benign

9.3

DANN

Uncertain

0.98

DEOGEN2

Benign

0.18

.;.;T

Eigen

Benign

-0.81

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.85

D;D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.78

D;D;D

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.3

M;M;M

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.1

N;N;N

REVEL

Uncertain

0.38

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

.;.;D

Vest4

0.81

MutPred

0.75

Gain of disorder (P = 0.0475);Gain of disorder (P = 0.0475);Gain of disorder (P = 0.0475);

MVP

0.20

MPC

1.2

ClinPred

0.55

GERP RS

-3.4

Varity_R

0.28

gMVP

0.53

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over