rs761671042

Variant names:

• chr4-25776316-A-G
• rs761671042
• NM_015187.5:c.2630T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015187.5(SEL1L3):​c.2630T>C​(p.Val877Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEL1L3 NM_015187.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.85

Genes affected

SEL1L3 (HGNC:29108): (SEL1L family member 3) Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEL1L3	NM_015187.5	c.2630T>C	p.Val877Ala	missense_variant	Exon 17 of 24	ENST00000399878.8	NP_056002.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEL1L3	ENST00000399878.8	c.2630T>C	p.Val877Ala	missense_variant	Exon 17 of 24	1	NM_015187.5	ENSP00000382767.3
SEL1L3	ENST00000264868.9	c.2525T>C	p.Val842Ala	missense_variant	Exon 17 of 24	1		ENSP00000264868.5
SEL1L3	ENST00000502949.5	c.2171T>C	p.Val724Ala	missense_variant	Exon 17 of 24	2		ENSP00000425438.1
SEL1L3	ENST00000509290.1	n.404T>C		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248760 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134980

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2630T>C (p.V877A) alteration is located in exon 17 (coding exon 17) of the SEL1L3 gene. This alteration results from a T to C substitution at nucleotide position 2630, causing the valine (V) at amino acid position 877 to be replaced by an alanine (A). 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	0.20
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T;.;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Uncertain	0.50	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.63	N;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.26	T;T;T
Sift4G	Uncertain	0.0090	D;T;T
Polyphen		0.35	B;.;.
Vest4		0.73
MutPred		0.64		Gain of disorder (P = 0.1038);.;.;
MVP		0.18
MPC		0.71
ClinPred		0.80	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.51

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

LitVar

Other links and lift over

dbSNP: rs761671042; hg19: chr4-25777938; COSMIC: COSV53550007; COSMIC: COSV53550007;