Genetic Variant NM_003105.6:c.*1483G>A (chr11-121631046-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003105.6(SORL1):c.*1483G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 154,146 control chromosomes in the GnomAD database, including 24,625 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 0.55 ( 24397 hom., cov: 32)

Exomes 𝑓: 0.46 ( 228 hom. )

Consequence

SORL1
NM_003105.6 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.510

Publications

17 publications found

Variant links:

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

SORL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6 link	c.*1483G>A		3_prime_UTR_variant	Exon 48 of 48	ENST00000260197.12	NP_003096.2	Q92673A0A024R3H2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12 link	c.*1483G>A		3_prime_UTR_variant	Exon 48 of 48	1	NM_003105.6	ENSP00000260197.6		Q92673
SORL1	ENST00000530365.1 link	n.759-970G>A		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.547

AC:

83106

AN:

151942

Hom.:

24343

Cov.:

show subpopulations

Gnomad AFR

AF:

0.751

Gnomad AMI

AF:

0.390

Gnomad AMR

AF:

0.542

Gnomad ASJ

AF:

0.404

Gnomad EAS

AF:

0.770

Gnomad SAS

AF:

0.556

Gnomad FIN

AF:

0.436

Gnomad MID

AF:

0.424

Gnomad NFE

AF:

0.435

Gnomad OTH

AF:

0.499

GnomAD4 exome

AF:

0.460

AC:

959

AN:

2086

Hom.:

228

Cov.:

AF XY:

0.438

AC XY:

498

AN XY:

1138

show subpopulations

African (AFR)

AF:

0.763

AC:

AN:

American (AMR)

AF:

0.586

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.466

AC:

AN:

East Asian (EAS)

AF:

0.719

AC:

217

AN:

302

South Asian (SAS)

AF:

0.357

AC:

AN:

European-Finnish (FIN)

AF:

0.349

AC:

AN:

232

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.399

AC:

515

AN:

1290

Other (OTH)

AF:

0.533

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

112

140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.547

AC:

83225

AN:

152060

Hom.:

24397

Cov.:

AF XY:

0.549

AC XY:

40772

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.751

AC:

31171

AN:

41500

American (AMR)

AF:

0.542

AC:

8282

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.404

AC:

1401

AN:

3466

East Asian (EAS)

AF:

0.769

AC:

3982

AN:

5178

South Asian (SAS)

AF:

0.554

AC:

2671

AN:

4818

European-Finnish (FIN)

AF:

0.436

AC:

4600

AN:

10560

Middle Eastern (MID)

AF:

0.442

AC:

130

AN:

294

European-Non Finnish (NFE)

AF:

0.435

AC:

29567

AN:

67942

Other (OTH)

AF:

0.506

AC:

1068

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1807

3614

5421

7228

9035

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

704

1408

2112

2816

3520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.469

Hom.:

32411

Bravo

AF:

0.564

Asia WGS

AF:

0.661

AC:

2302

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

2.9

(source)

DANN

Benign

0.69

PhyloP100

0.51

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over