1-109336296-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002959.7(SORT1):c.1315C>T(p.His439Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SORT1 NM_002959.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.52

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2670428).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORT1	NM_002959.7	c.1315C>T	p.His439Tyr	missense_variant	11/20	ENST00000256637.8
SORT1	NM_001205228.2	c.904C>T	p.His302Tyr	missense_variant	11/20
SORT1	XM_005271100.3	c.1312C>T	p.His438Tyr	missense_variant	11/20
SORT1	XM_005271101.4	c.907C>T	p.His303Tyr	missense_variant	11/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORT1	ENST00000256637.8	c.1315C>T	p.His439Tyr	missense_variant	11/20	1	NM_002959.7	P1
SORT1	ENST00000538502.5	c.904C>T	p.His302Tyr	missense_variant	11/20	2
SORT1	ENST00000466471.1	n.7C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2023

The c.1315C>T (p.H439Y) alteration is located in exon 11 (coding exon 11) of the SORT1 gene. This alteration results from a C to T substitution at nucleotide position 1315, causing the histidine (H) at amino acid position 439 to be replaced by a tyrosine (Y). 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	0.080
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
Cadd	Uncertain	24
Dann	Benign	0.47
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.033
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.92	N;N
REVEL	Benign	0.18
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0050	.;B
Vest4		0.36
MutPred		0.45		.;Loss of disorder (P = 0.0515);
MVP		0.16
MPC		0.28
ClinPred		0.40	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
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

Other links and lift over

dbSNP: rs1648820781; hg19: chr1-109878918;