11-121452568-G-A

Position:

• chr11-121452568-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_003105.6(SORL1):​c.237G>A​(p.Arg79=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,518,978 control chromosomes in the GnomAD database, including 266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (61 hom., cov: 32)
  • Exomes 𝑓: 0.014 (205 hom.)
• Consequence: SORL1 NM_003105.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.00

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 11-121452568-G-A is Benign according to our data. Variant chr11-121452568-G-A is described in ClinVar as [Benign]. Clinvar id is 1210033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-121452568-G-A is described in Lovd as [Benign]. Variant chr11-121452568-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0234 (3564/152246) while in subpopulation AFR AF= 0.0377 (1565/41560). AF 95% confidence interval is 0.0361. There are 61 homozygotes in gnomad4. There are 1861 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 61 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORL1	NM_003105.6	c.237G>A	p.Arg79=	synonymous_variant	1/48	ENST00000260197.12
SORL1-AS1	NR_183636.1	n.293+107C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORL1	ENST00000260197.12	c.237G>A	p.Arg79=	synonymous_variant	1/48	1	NM_003105.6	P1
SORL1	ENST00000532451.1	n.189G>A		non_coding_transcript_exon_variant	1/15	1
SORL1-AS1	ENST00000501964.1	n.339+107C>T		intron_variant, non_coding_transcript_variant		2
SORL1-AS1	ENST00000529160.1	n.245+107C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3560 AN: 152128 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.0377

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.00808

Gnomad EAS AF: 0.00542

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.0601

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.0133 AC: 1857 AN: 139538 Hom.: 20 AF XY: 0.0132 AC XY: 1050 AN XY: 79376

Gnomad AFR exome AF: 0.0365

Gnomad AMR exome AF: 0.00611

Gnomad ASJ exome AF: 0.00878

Gnomad EAS exome AF: 0.00408

Gnomad SAS exome AF: 0.00955

Gnomad FIN exome AF: 0.0522

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.0125

GnomAD4 exome AF: 0.0136 AC: 18607 AN: 1366732 Hom.: 205 Cov.: 31 AF XY: 0.0136 AC XY: 9174 AN XY: 676176

Gnomad4 AFR exome AF: 0.0370

Gnomad4 AMR exome AF: 0.00696

Gnomad4 ASJ exome AF: 0.00855

Gnomad4 EAS exome AF: 0.00279

Gnomad4 SAS exome AF: 0.0106

Gnomad4 FIN exome AF: 0.0524

Gnomad4 NFE exome AF: 0.0126

Gnomad4 OTH exome AF: 0.0146

GnomAD4 genome AF: 0.0234 AC: 3564 AN: 152246 Hom.: 61 Cov.: 32 AF XY: 0.0250 AC XY: 1861 AN XY: 74464

Gnomad4 AFR AF: 0.0377

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.00808

Gnomad4 EAS AF: 0.00543

Gnomad4 SAS AF: 0.0101

Gnomad4 FIN AF: 0.0601

Gnomad4 NFE AF: 0.0143

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0182 Hom.: 4

Bravo AF: 0.0206

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Uncertain	0.98

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

LitVar

Other links and lift over

dbSNP: rs114331262; hg19: chr11-121323277;