NM_002959.7:c.1175G>T

Variant names:

• chr1-109340813-C-A
• NM_002959.7:c.1175G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002959.7(SORT1):​c.1175G>T​(p.Arg392Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 5.95

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORT1	NM_002959.7	c.1175G>T	p.Arg392Leu	missense_variant	Exon 10 of 20	ENST00000256637.8	NP_002950.3
SORT1	NM_001205228.2	c.764G>T	p.Arg255Leu	missense_variant	Exon 10 of 20		NP_001192157.1
SORT1	XM_005271100.3	c.1172G>T	p.Arg391Leu	missense_variant	Exon 10 of 20		XP_005271157.1
SORT1	XM_005271101.4	c.767G>T	p.Arg256Leu	missense_variant	Exon 10 of 20		XP_005271158.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORT1	ENST00000256637.8	c.1175G>T	p.Arg392Leu	missense_variant	Exon 10 of 20	1	NM_002959.7	ENSP00000256637.6
SORT1	ENST00000538502.5	c.764G>T	p.Arg255Leu	missense_variant	Exon 10 of 20	2		ENSP00000438597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1175G>T (p.R392L) alteration is located in exon 10 (coding exon 10) of the SORT1 gene. This alteration results from a G to T substitution at nucleotide position 1175, causing the arginine (R) at amino acid position 392 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	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	.;D
Vest4		0.87
MutPred		0.53		.;Gain of sheet (P = 0.0827);
MVP		0.63
MPC		0.92
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-109883435;