4-25788279-G-A

Position:

• chr4-25788279-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015187.5(SEL1L3):​c.2162C>T​(p.Ala721Val) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SEL1L3 NM_015187.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.96

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEL1L3	NM_015187.5	c.2162C>T	p.Ala721Val	missense_variant	13/24	ENST00000399878.8	NP_056002.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEL1L3	ENST00000399878.8	c.2162C>T	p.Ala721Val	missense_variant	13/24	1	NM_015187.5	ENSP00000382767.3
SEL1L3	ENST00000264868.9	c.2057C>T	p.Ala686Val	missense_variant	13/24	1		ENSP00000264868.5
SEL1L3	ENST00000502949.5	c.1703C>T	p.Ala568Val	missense_variant	13/24	2		ENSP00000425438.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Nov 24, 2024

The c.2162C>T (p.A721V) alteration is located in exon 13 (coding exon 13) of the SEL1L3 gene. This alteration results from a C to T substitution at nucleotide position 2162, causing the alanine (A) at amino acid position 721 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	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.0	M;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0050	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.93
MutPred		0.59		Loss of disorder (P = 0.1115);.;.;
MVP		0.37
MPC		0.73
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.40
gMVP		0.77

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.

Other links and lift over

hg19: chr4-25789901; COSMIC: COSV99339723;