NM_003105.6:c.6171+24T>G

Variant names:

• chr11-121622292-T-G
• rs1614735
• NM_003105.6:c.6171+24T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003105.6(SORL1):​c.6171+24T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 1,372,548 control chromosomes in the GnomAD database, including 153,593 homozygotes. 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: 𝑓 0.37 (12346 hom., cov: 32)
  • Exomes 𝑓: 0.47 (141247 hom.)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14
• Publications: 23 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 Gene-Disease associations (from GenCC):

• early-onset autosomal dominant Alzheimer disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.6171+24T>G		intron_variant	Intron 45 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.6171+24T>G		intron_variant	Intron 45 of 47	1	NM_003105.6	ENSP00000260197.6

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55891 AN: 151828 Hom.: 12354 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.577

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.416

GnomAD2 exomes AF: 0.405 AC: 97765 AN: 241624 AF XY: 0.412

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.348

Gnomad ASJ exome AF: 0.570

Gnomad EAS exome AF: 0.126

Gnomad FIN exome AF: 0.451

Gnomad NFE exome AF: 0.499

Gnomad OTH exome AF: 0.457

GnomAD4 exome AF: 0.470 AC: 573500 AN: 1220602 Hom.: 141247 Cov.: 16 AF XY: 0.467 AC XY: 288812 AN XY: 618314

African (AFR) AF: 0.121 AC: 3450 AN: 28434

American (AMR) AF: 0.358 AC: 15266 AN: 42674

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 14083 AN: 24402

East Asian (EAS) AF: 0.143 AC: 5484 AN: 38478

South Asian (SAS) AF: 0.346 AC: 27768 AN: 80260

European-Finnish (FIN) AF: 0.449 AC: 23157 AN: 51556

Middle Eastern (MID) AF: 0.457 AC: 2396 AN: 5242

European-Non Finnish (NFE) AF: 0.511 AC: 458285 AN: 897354

Other (OTH) AF: 0.452 AC: 23611 AN: 52202

GnomAD4 genome AF: 0.368 AC: 55887 AN: 151946 Hom.: 12346 Cov.: 32 AF XY: 0.365 AC XY: 27117 AN XY: 74238

African (AFR) AF: 0.134 AC: 5541 AN: 41468

American (AMR) AF: 0.377 AC: 5759 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 2002 AN: 3468

East Asian (EAS) AF: 0.135 AC: 697 AN: 5176

South Asian (SAS) AF: 0.343 AC: 1654 AN: 4824

European-Finnish (FIN) AF: 0.443 AC: 4648 AN: 10484

Middle Eastern (MID) AF: 0.510 AC: 149 AN: 292

European-Non Finnish (NFE) AF: 0.501 AC: 34010 AN: 67930

Other (OTH) AF: 0.412 AC: 869 AN: 2110

Alfa AF: 0.459 Hom.: 29098

Bravo AF: 0.355

Asia WGS AF: 0.245 AC: 850 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.90
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs1614735; hg19: chr11-121493001; COSMIC: COSV52753605; COSMIC: COSV52753605;