11-121452530-A-C

Variant names:

• chr11-121452530-A-C
• rs911407554
• NM_003105.6:c.199A>C
• SORL1 p.Arg67Arg

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_003105.6(SORL1):​c.199A>C​(p.Arg67Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000225 in 1,331,758 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: SORL1 NM_003105.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.572
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP7: Synonymous conserved (PhyloP=-0.572 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003105.6. 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
	SORL1	NM_003105.6	MANE Select	c.199A>C	p.Arg67Arg	synonymous	Exon 1 of 48	NP_003096.2	Q92673
	SORL1-AS1	NR_183636.1	MANE Select	n.293+145T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	ENST00000260197.12	TSL:1 MANE Select	c.199A>C	p.Arg67Arg	synonymous	Exon 1 of 48	ENSP00000260197.6	Q92673
	SORL1	ENST00000532451.1	TSL:1	n.151A>C		non_coding_transcript_exon	Exon 1 of 15
	SORL1-AS1	ENST00000529160.2	TSL:2 MANE Select	n.293+145T>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000225 AC: 3 AN: 1331758 Hom.: 0 Cov.: 31 AF XY: 0.00000152 AC XY: 1 AN XY: 655794

African (AFR) AF: 0.00 AC: 0 AN: 27136

American (AMR) AF: 0.00 AC: 0 AN: 27716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22526

East Asian (EAS) AF: 0.00 AC: 0 AN: 30694

South Asian (SAS) AF: 0.00 AC: 0 AN: 73284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4804

European-Non Finnish (NFE) AF: 0.00000190 AC: 2 AN: 1054842

Other (OTH) AF: 0.0000181 AC: 1 AN: 55260

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.78
PhyloP100		-0.57
PromoterAI		0.0046	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs911407554; hg19: chr11-121323239;