14-81499465-C-T

Variant names:

• chr14-81499465-C-T
• rs1230003756
• NM_005065.6:c.885G>A

Variant summary

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

The NM_005065.6(SEL1L):​c.885G>A​(p.Met295Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,712 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: 6.9e-7 (0 hom.)
• Consequence: SEL1L NM_005065.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.33
• Publications: 0 publications found

Genes affected

SEL1L (HGNC:10717): (SEL1L adaptor subunit of SYVN1 ubiquitin ligase) The protein encoded by this gene is part of a protein complex required for the retrotranslocation or dislocation of misfolded proteins from the endoplasmic reticulum lumen to the cytosol, where they are degraded by the proteasome in a ubiquitin-dependent manner. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

SEL1L Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia

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, 0.811

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005065.6. 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
	SEL1L	NM_005065.6	MANE Select	c.885G>A	p.Met295Ile	missense	Exon 8 of 21	NP_005056.3
	SEL1L	NM_001244984.2		c.885G>A	p.Met295Ile	missense	Exon 8 of 8	NP_001231913.1	Q9UBV2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEL1L	ENST00000336735.9	TSL:1 MANE Select	c.885G>A	p.Met295Ile	missense	Exon 8 of 21	ENSP00000337053.4	Q9UBV2-1
	SEL1L	ENST00000555824.5	TSL:1	c.885G>A	p.Met295Ile	missense	Exon 8 of 8	ENSP00000450709.1	Q9UBV2-2
	SEL1L	ENST00000870907.1		c.885G>A	p.Met295Ile	missense	Exon 8 of 22	ENSP00000540966.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249012 AF XY: 0.00

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458712 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725606

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

African (AFR) AF: 0.0000300 AC: 1 AN: 33294

American (AMR) AF: 0.00 AC: 0 AN: 44158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.00 AC: 0 AN: 85574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5434

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111028

Other (OTH) AF: 0.00 AC: 0 AN: 60254

⚠️ 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.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.79	P
Vest4		0.88
MutPred		0.46		Loss of helix (P = 0.2271)
MVP		0.58
MPC		0.58
ClinPred		0.89	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.85
Mutation Taster		=22/78	disease causing

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: rs1230003756; hg19: chr14-81965809;