Variant 4-25776329-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015187.5(SEL1L3):c.2617T>C(p.Tyr873His) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,613,224 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y873F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SEL1L3
NM_015187.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.03

Variant links:

Genes affected

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

SEL1L3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08842218).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEL1L3	NM_015187.5 linkuse as main transcript	c.2617T>C	p.Tyr873His	missense_variant	17/24	ENST00000399878.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEL1L3	ENST00000399878.8 linkuse as main transcript	c.2617T>C	p.Tyr873His	missense_variant	17/24	1	NM_015187.5	P1	Q68CR1-1
SEL1L3	ENST00000264868.9 linkuse as main transcript	c.2512T>C	p.Tyr838His	missense_variant	17/24	1			Q68CR1-2
SEL1L3	ENST00000502949.5 linkuse as main transcript	c.2158T>C	p.Tyr720His	missense_variant	17/24	2			Q68CR1-3
SEL1L3	ENST00000509290.1 linkuse as main transcript	n.391T>C		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000523

AC:

AN:

248650

Hom.:

AF XY:

0.0000519

AC XY:

AN XY:

134924

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000613

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1460934

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726788

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000662

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2023

The c.2617T>C (p.Y873H) 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 2617, causing the tyrosine (Y) at amino acid position 873 to be replaced by a histidine (H). 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

0.17

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.36

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.0079

T;.;.

Eigen

Benign

-0.11

Eigen_PC

Benign

0.076

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.0056

MetaRNN

Benign

0.088

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.;.

MutationTaster

Benign

0.89

D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.79

N;N;N

REVEL

Benign

0.11

Sift

Benign

0.23

T;T;T

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

0.53

P;.;.

Vest4

0.55

MutPred

0.55

Gain of disorder (P = 0.0084);.;.;

MVP

0.043

MPC

0.25

ClinPred

0.085

GERP RS

4.9

Varity_R

0.052

gMVP

0.46

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over