1-109323100-A-C

Variant names:

• chr1-109323100-A-C
• NM_002959.7:c.1856T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002959.7(SORT1):​c.1856T>G​(p.Ile619Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,688 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. I619T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SORT1 NM_002959.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.11

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18495348).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORT1	NM_002959.7	c.1856T>G	p.Ile619Arg	missense_variant	Exon 15 of 20	ENST00000256637.8	NP_002950.3
SORT1	NM_001205228.2	c.1445T>G	p.Ile482Arg	missense_variant	Exon 15 of 20		NP_001192157.1
SORT1	XM_005271100.3	c.1853T>G	p.Ile618Arg	missense_variant	Exon 15 of 20		XP_005271157.1
SORT1	XM_005271101.4	c.1448T>G	p.Ile483Arg	missense_variant	Exon 15 of 20		XP_005271158.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORT1	ENST00000256637.8	c.1856T>G	p.Ile619Arg	missense_variant	Exon 15 of 20	1	NM_002959.7	ENSP00000256637.6
SORT1	ENST00000538502.5	c.1445T>G	p.Ile482Arg	missense_variant	Exon 15 of 20	2		ENSP00000438597.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461688 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727170

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.057	.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.27	.;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.13	N;N
REVEL	Benign	0.11
Sift	Benign	0.51	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.063	.;B
Vest4		0.45
MutPred		0.56		.;Gain of disorder (P = 0.0351);
MVP		0.22
MPC		0.44
ClinPred		0.21	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-109865722;