4-25776328-T-A

Variant summary

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

The NM_015187.5(SEL1L3):c.2618A>T(p.Tyr873Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,460,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y873H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SEL1L3 NM_015187.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.75

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=0.34793168).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEL1L3	NM_015187.5	c.2618A>T	p.Tyr873Phe	missense_variant	17/24	ENST00000399878.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEL1L3	ENST00000399878.8	c.2618A>T	p.Tyr873Phe	missense_variant	17/24	1	NM_015187.5	P1
SEL1L3	ENST00000264868.9	c.2513A>T	p.Tyr838Phe	missense_variant	17/24	1
SEL1L3	ENST00000502949.5	c.2159A>T	p.Tyr720Phe	missense_variant	17/24	2
SEL1L3	ENST00000509290.1	n.392A>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460960 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 726790

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000810

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

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

Jul 12, 2023

The c.2618A>T (p.Y873F) alteration is located in exon 17 (coding exon 17) of the SEL1L3 gene. This alteration results from a A to T substitution at nucleotide position 2618, causing the tyrosine (Y) at amino acid position 873 to be replaced by a phenylalanine (F). 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	0.11
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	24
Dann	Benign	0.97
DEOGEN2	Benign	0.020	T;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.0	M;.;.
MutationTaster	Benign	0.89	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.098	T;T;T
Sift4G	Benign	0.12	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.57
MutPred		0.54		Loss of ubiquitination at K870 (P = 0.0801);.;.;
MVP		0.34
MPC		0.43
ClinPred		0.83	D
GERP RS		6.1
Varity_R		0.17
gMVP		0.26

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: rs779548874; hg19: chr4-25777950;