chr11-121452568-G-A

Variant names:

• chr11-121452568-G-A
• rs114331262
• NM_003105.6:c.237G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_003105.6(SORL1):​c.237G>A​(p.Arg79Arg) 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
• Publications: 2 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: Benign. The variant received -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 VariationId is 1210033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3564 AD gene.

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.237G>A	p.Arg79Arg	synonymous	Exon 1 of 48	NP_003096.2	Q92673
	SORL1-AS1	NR_183636.1	MANE Select	n.293+107C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	ENST00000260197.12	TSL:1 MANE Select	c.237G>A	p.Arg79Arg	synonymous	Exon 1 of 48	ENSP00000260197.6	Q92673
	SORL1	ENST00000532451.1	TSL:1	n.189G>A		non_coding_transcript_exon	Exon 1 of 15
	SORL1-AS1	ENST00000529160.2	TSL:2 MANE Select	n.293+107C>T		intron	N/A

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

GnomAD2 exomes AF: 0.0133 AC: 1857 AN: 139538 AF XY: 0.0132

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 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

African (AFR) AF: 0.0370 AC: 1044 AN: 28192

American (AMR) AF: 0.00696 AC: 234 AN: 33644

Ashkenazi Jewish (ASJ) AF: 0.00855 AC: 203 AN: 23756

East Asian (EAS) AF: 0.00279 AC: 91 AN: 32590

South Asian (SAS) AF: 0.0106 AC: 822 AN: 77450

European-Finnish (FIN) AF: 0.0524 AC: 1869 AN: 35670

Middle Eastern (MID) AF: 0.00669 AC: 37 AN: 5532

European-Non Finnish (NFE) AF: 0.0126 AC: 13477 AN: 1073150

Other (OTH) AF: 0.0146 AC: 830 AN: 56748

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

African (AFR) AF: 0.0377 AC: 1565 AN: 41560

American (AMR) AF: 0.0146 AC: 223 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00808 AC: 28 AN: 3466

East Asian (EAS) AF: 0.00543 AC: 28 AN: 5156

South Asian (SAS) AF: 0.0101 AC: 49 AN: 4832

European-Finnish (FIN) AF: 0.0601 AC: 638 AN: 10610

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0143 AC: 975 AN: 67996

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.0178 Hom.: 4

Bravo AF: 0.0206

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Uncertain	0.98
PhyloP100		1.0
PromoterAI		-0.045	Neutral
Mutation Taster		=100/0	polymorphism

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: rs114331262; hg19: chr11-121323277; COSMIC: COSV107279363;