NM_015187.5:c.3152G>C

Variant names:

• chr4-25757722-C-G
• rs913079679
• NM_015187.5:c.3152G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015187.5(SEL1L3):​c.3152G>C​(p.Arg1051Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,446,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R1051Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SEL1L3 NM_015187.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.42
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

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.3152G>C	p.Arg1051Pro	missense	Exon 22 of 24	NP_056002.2	Q68CR1-1
	SEL1L3	NM_001297592.2		c.3047G>C	p.Arg1016Pro	missense	Exon 22 of 24	NP_001284521.1	Q68CR1-2
	SEL1L3	NM_001297594.2		c.2693G>C	p.Arg898Pro	missense	Exon 22 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.3152G>C	p.Arg1051Pro	missense	Exon 22 of 24	ENSP00000382767.3	Q68CR1-1
	SEL1L3	ENST00000264868.9	TSL:1	c.3047G>C	p.Arg1016Pro	missense	Exon 22 of 24	ENSP00000264868.5	Q68CR1-2
	SEL1L3	ENST00000929301.1		c.3257G>C	p.Arg1086Pro	missense	Exon 22 of 24	ENSP00000599360.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1446026 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 717510

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33212

American (AMR) AF: 0.00 AC: 0 AN: 42552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25750

East Asian (EAS) AF: 0.00 AC: 0 AN: 38940

South Asian (SAS) AF: 0.00 AC: 0 AN: 83070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104580

Other (OTH) AF: 0.00 AC: 0 AN: 59874

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0099	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.22
Sift	Uncertain	0.013	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.65		Loss of methylation at R1051 (P = 0.0289)
MVP		0.13
MPC		0.29
ClinPred		0.94	D
GERP RS		5.6
Varity_R		0.67
gMVP		0.85
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs913079679; hg19: chr4-25759344;