4-25788280-C-T

Variant summary

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

The NM_015187.5(SEL1L3):c.2161G>A(p.Ala721Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,644 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: 0.0000055 (0 hom.)
• Consequence: SEL1L3 NM_015187.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.30

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, 0.842

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEL1L3	NM_015187.5	c.2161G>A	p.Ala721Thr	missense_variant	13/24	ENST00000399878.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEL1L3	ENST00000399878.8	c.2161G>A	p.Ala721Thr	missense_variant	13/24	1	NM_015187.5	P1
SEL1L3	ENST00000264868.9	c.2056G>A	p.Ala686Thr	missense_variant	13/24	1
SEL1L3	ENST00000502949.5	c.1702G>A	p.Ala568Thr	missense_variant	13/24	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248910 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 135002

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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 AF: 0.00000547 AC: 8 AN: 1461644 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Feb 27, 2024

The c.2161G>A (p.A721T) alteration is located in exon 13 (coding exon 13) of the SEL1L3 gene. This alteration results from a G to A substitution at nucleotide position 2161, causing the alanine (A) at amino acid position 721 to be replaced by a threonine (T). 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	0.19	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.23	T;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.0	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.96
MutPred		0.59		Gain of ubiquitination at K719 (P = 0.0725);.;.;
MVP		0.30
MPC		0.72
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.52
gMVP		0.71

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: rs767645920; hg19: chr4-25789902; COSMIC: COSV53541674;