Variant rs72646588 details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_002959.7(SORT1):c.2237G>T(p.Ser746Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000747 in 1,605,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S746N) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

SORT1
NM_002959.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.554

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07649639).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORT1	NM_002959.7 link	c.2237G>T	p.Ser746Ile	missense_variant	Exon 17 of 20	ENST00000256637.8	NP_002950.3	Q99523-1
SORT1	NM_001205228.2 link	c.1826G>T	p.Ser609Ile	missense_variant	Exon 17 of 20		NP_001192157.1	Q99523-2
SORT1	XM_005271100.3 link	c.2234G>T	p.Ser745Ile	missense_variant	Exon 17 of 20		XP_005271157.1
SORT1	XM_005271101.4 link	c.1829G>T	p.Ser610Ile	missense_variant	Exon 17 of 20		XP_005271158.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SORT1	ENST00000256637.8 link	c.2237G>T	p.Ser746Ile	missense_variant	Exon 17 of 20	1	NM_002959.7	ENSP00000256637.6	Q99523-1
SORT1	ENST00000538502.5 link	c.1826G>T	p.Ser609Ile	missense_variant	Exon 17 of 20	2		ENSP00000438597.1	Q99523-2
SORT1	ENST00000485149.1 link	n.65G>T		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000688

AC:

AN:

1453730

Hom.:

Cov.:

AF XY:

0.00000968

AC XY:

AN XY:

723272

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000903

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.21

.;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.65

T;T

M_CAP

Benign

0.0078

MetaRNN

Benign

0.076

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.0

.;L

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.039

Sift

Benign

0.23

T;T

Sift4G

Benign

0.092

T;T

Polyphen

0.16

.;B

Vest4

0.090

MutPred

0.33

.;Loss of disorder (P = 0.0022);

MVP

0.21

MPC

0.95

ClinPred

0.21

GERP RS

3.4

Varity_R

0.19

gMVP

0.85

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over