4-25748441-G-T

Variant names:

• chr4-25748441-G-T
• rs746867162
• NM_015187.5:c.3383C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015187.5(SEL1L3):​c.3383C>A​(p.Pro1128Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1128L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SEL1L3 NM_015187.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.562
• Publications: 0 publications found

Genes affected

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0526098).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015187.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEL1L3	NM_015187.5	MANE Select	c.3383C>A	p.Pro1128Gln	missense	Exon 24 of 24	NP_056002.2	Q68CR1-1
	SEL1L3	NM_001297592.2		c.3278C>A	p.Pro1093Gln	missense	Exon 24 of 24	NP_001284521.1	Q68CR1-2
	SEL1L3	NM_001297594.2		c.2924C>A	p.Pro975Gln	missense	Exon 24 of 24	NP_001284523.1	Q68CR1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEL1L3	ENST00000399878.8	TSL:1 MANE Select	c.3383C>A	p.Pro1128Gln	missense	Exon 24 of 24	ENSP00000382767.3	Q68CR1-1
	SEL1L3	ENST00000264868.9	TSL:1	c.3278C>A	p.Pro1093Gln	missense	Exon 24 of 24	ENSP00000264868.5	Q68CR1-2
	SEL1L3	ENST00000929301.1		c.3488C>A	p.Pro1163Gln	missense	Exon 24 of 24	ENSP00000599360.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458202 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724922

African (AFR) AF: 0.0000299 AC: 1 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 85178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110572

Other (OTH) AF: 0.00 AC: 0 AN: 60290

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.8
DANN	Benign	0.65
DEOGEN2	Benign	0.0067	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.56
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.059
Sift	Uncertain	0.010	D
Sift4G	Benign	0.29	T
Polyphen		0.30	B
Vest4		0.15
MutPred		0.17		Loss of catalytic residue at P1128 (P = 0.0174)
MVP		0.043
MPC		0.28
ClinPred		0.14	T
GERP RS		0.14
Varity_R		0.030
gMVP		0.28
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs746867162; hg19: chr4-25750063;