chr4-25776326-A-C

Position:

• chr4-25776326-A-C

Variant summary

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

The NM_015187.5(SEL1L3):​c.2620T>G​(p.Leu874Val) 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. 13/21 in silico tools predict a benign outcome for this variant. 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: 0.698

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33062255).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEL1L3	NM_015187.5	c.2620T>G	p.Leu874Val	missense_variant	17/24	ENST00000399878.8	NP_056002.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEL1L3	ENST00000399878.8	c.2620T>G	p.Leu874Val	missense_variant	17/24	1	NM_015187.5	ENSP00000382767.3
SEL1L3	ENST00000264868.9	c.2515T>G	p.Leu839Val	missense_variant	17/24	1		ENSP00000264868.5
SEL1L3	ENST00000502949.5	c.2161T>G	p.Leu721Val	missense_variant	17/24	2		ENSP00000425438.1
SEL1L3	ENST00000509290.1	n.394T>G		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

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

Apr 29, 2024

The c.2620T>G (p.L874V) alteration is located in exon 17 (coding exon 17) of the SEL1L3 gene. This alteration results from a T to G substitution at nucleotide position 2620, causing the leucine (L) at amino acid position 874 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	0.22
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	T;.;.
Eigen	Benign	0.071
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.7	L;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.019	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.60
MutPred		0.32		Gain of MoRF binding (P = 0.0917);.;.;
MVP		0.28
MPC		0.67
ClinPred		0.94	D
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr4-25777948;