Genetic Variant SORT1:p.Ile547Leu (chr1-109326996-T-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002959.7(SORT1):c.1639A>C(p.Ile547Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,610,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

SORT1
NM_002959.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.71

Variant links:

Genes affected

SORT1 (HGNC:11186): (sortilin 1) This gene encodes a member of the VPS10-related sortilin family of proteins. The encoded preproprotein is proteolytically processed by furin to generate the mature receptor. This receptor plays a role in the trafficking of different proteins to either the cell surface, or subcellular compartments such as lysosomes and endosomes. Expression levels of this gene may influence the risk of myocardial infarction in human patients. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

SORT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.164875).

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORT1	NM_002959.7 link	c.1639A>C	p.Ile547Leu	missense_variant	Exon 13 of 20	ENST00000256637.8	NP_002950.3	Q99523-1
SORT1	NM_001205228.2 link	c.1228A>C	p.Ile410Leu	missense_variant	Exon 13 of 20		NP_001192157.1	Q99523-2
SORT1	XM_005271100.3 link	c.1636A>C	p.Ile546Leu	missense_variant	Exon 13 of 20		XP_005271157.1
SORT1	XM_005271101.4 link	c.1231A>C	p.Ile411Leu	missense_variant	Exon 13 of 20		XP_005271158.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SORT1	ENST00000256637.8 link	c.1639A>C	p.Ile547Leu	missense_variant	Exon 13 of 20	1	NM_002959.7	ENSP00000256637.6	Q99523-1
SORT1	ENST00000538502.5 link	c.1228A>C	p.Ile410Leu	missense_variant	Exon 13 of 20	2		ENSP00000438597.1	Q99523-2
SORT1	ENST00000466471.1 link	n.331A>C		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.0000320

AC:

AN:

249940

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135028

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1458568

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725542

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000202

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000957

Bravo

AF:

0.0000642

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1639A>C (p.I547L) alteration is located in exon 13 (coding exon 13) of the SORT1 gene. This alteration results from a A to C substitution at nucleotide position 1639, causing the isoleucine (I) at amino acid position 547 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.075

.;T

Eigen

Benign

-0.15

Eigen_PC

Benign

0.082

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.0041

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;L

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.90

N;N

REVEL

Benign

0.096

Sift

Benign

0.085

T;T

Sift4G

Benign

0.15

T;T

Polyphen

0.064

.;B

Vest4

0.42

MutPred

0.37

.;Loss of methylation at K548 (P = 0.0584);

MVP

0.20

MPC

0.26

ClinPred

0.077

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.69

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over