11-121452394-G-C

Variant names:

• chr11-121452394-G-C
• NM_003105.6:c.63G>C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_003105.6(SORL1):​c.63G>C​(p.Leu21Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,387,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L21L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SORL1 NM_003105.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.73

Genes affected

SORL1 (HGNC:11185): (sortilin related receptor 1) This gene encodes a mosaic protein that belongs to at least two families: the vacuolar protein sorting 10 (VPS10) domain-containing receptor family, and the low density lipoprotein receptor (LDLR) family. The encoded protein also contains fibronectin type III repeats and an epidermal growth factor repeat. The encoded preproprotein is proteolytically processed to generate the mature receptor, which likely plays roles in endocytosis and sorting. Mutations in this gene may be associated with Alzheimer's disease. [provided by RefSeq, Feb 2016]

SORL1-AS1 (HGNC:55594): (SORL1 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP7: Synonymous conserved (PhyloP=1.73 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.63G>C	p.Leu21Leu	synonymous_variant	Exon 1 of 48	ENST00000260197.12	NP_003096.2
SORL1-AS1	NR_183636.1	n.293+281C>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.63G>C	p.Leu21Leu	synonymous_variant	Exon 1 of 48	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000532451.1	n.15G>C		non_coding_transcript_exon_variant	Exon 1 of 15	1
SORL1-AS1	ENST00000501964.1	n.339+281C>G		intron_variant	Intron 1 of 1	2
SORL1-AS1	ENST00000529160.1	n.245+281C>G		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1387112 Hom.: 0 Cov.: 30 AF XY: 0.00000292 AC XY: 2 AN XY: 686038

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.0000175

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	15
DANN	Benign	0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-121323103;