Variant chr1-109316858-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002959.7(SORT1):c.2242G>C(p.Glu748Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,449,348 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

SORT1
NM_002959.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.111

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:

SORT1 (HGNC:):

SORT1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09612617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SORT1	NM_002959.7 linkuse as main transcript	c.2242G>C	p.Glu748Gln	missense_variant	17/20	ENST00000256637.8	NP_002950.3	Q99523-1
SORT1	NM_001205228.2 linkuse as main transcript	c.1831G>C	p.Glu611Gln	missense_variant	17/20		NP_001192157.1	Q99523-2
SORT1	XM_005271100.3 linkuse as main transcript	c.2239G>C	p.Glu747Gln	missense_variant	17/20		XP_005271157.1
SORT1	XM_005271101.4 linkuse as main transcript	c.1834G>C	p.Glu612Gln	missense_variant	17/20		XP_005271158.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SORT1	ENST00000256637.8 linkuse as main transcript	c.2242G>C	p.Glu748Gln	missense_variant	17/20	1	NM_002959.7	ENSP00000256637.6	Q99523-1
SORT1	ENST00000538502.5 linkuse as main transcript	c.1831G>C	p.Glu611Gln	missense_variant	17/20	2		ENSP00000438597.1	Q99523-2
SORT1	ENST00000485149.1 linkuse as main transcript	n.70G>C		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1449348

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721528

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:

0.00000362

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2024

The c.2242G>C (p.E748Q) alteration is located in exon 17 (coding exon 17) of the SORT1 gene. This alteration results from a G to C substitution at nucleotide position 2242, causing the glutamic acid (E) at amino acid position 748 to be replaced by a glutamine (Q). 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

0.070

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.12

.;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.61

T;T

M_CAP

Benign

0.0083

MetaRNN

Benign

0.096

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.1

.;L

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.27

N;N

REVEL

Benign

0.10

Sift

Benign

0.33

T;T

Sift4G

Benign

0.46

T;T

Polyphen

0.0030

.;B

Vest4

0.13

MutPred

0.16

.;Loss of ubiquitination at K749 (P = 0.0119);

MVP

0.40

MPC

0.79

ClinPred

0.089

GERP RS

2.4

Varity_R

0.38

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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