1-109342050-C-A

Position:

• chr1-109342050-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002959.7(SORT1):​c.1072G>T​(p.Asp358Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00172 in 1,613,918 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (6 hom.)
• Consequence: SORT1 NM_002959.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.35

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008756906).
• BP6: Variant 1-109342050-C-A is Benign according to our data. Variant chr1-109342050-C-A is described in ClinVar as [Benign]. Clinvar id is 789875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00161 (246/152340) while in subpopulation EAS AF= 0.0191 (99/5186). AF 95% confidence interval is 0.016. There are 2 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 246 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SORT1	NM_002959.7	c.1072G>T	p.Asp358Tyr	missense_variant	9/20	ENST00000256637.8	NP_002950.3
SORT1	NM_001205228.2	c.661G>T	p.Asp221Tyr	missense_variant	9/20		NP_001192157.1
SORT1	XM_005271100.3	c.1069G>T	p.Asp357Tyr	missense_variant	9/20		XP_005271157.1
SORT1	XM_005271101.4	c.664G>T	p.Asp222Tyr	missense_variant	9/20		XP_005271158.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SORT1	ENST00000256637.8	c.1072G>T	p.Asp358Tyr	missense_variant	9/20	1	NM_002959.7	ENSP00000256637	P1
SORT1	ENST00000538502.5	c.661G>T	p.Asp221Tyr	missense_variant	9/20	2		ENSP00000438597

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 246 AN: 152222 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.0190

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00237 AC: 596 AN: 251412 Hom.: 4 AF XY: 0.00244 AC XY: 331 AN XY: 135868

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.0158

Gnomad SAS exome AF: 0.00183

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00163

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00173 AC: 2529 AN: 1461578 Hom.: 6 Cov.: 31 AF XY: 0.00175 AC XY: 1275 AN XY: 727080

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.0157

Gnomad4 SAS exome AF: 0.00152

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.00139

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.00161 AC: 246 AN: 152340 Hom.: 2 Cov.: 32 AF XY: 0.00166 AC XY: 124 AN XY: 74496

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.0191

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00222 Hom.: 3

Bravo AF: 0.00185

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00262 AC: 318

Asia WGS AF: 0.00751 AC: 27 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00172

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	.;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
MetaRNN	Benign	0.0088	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.9	.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Benign	0.19
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.98	.;D
Vest4		0.77
MVP		0.67
MPC		0.34
ClinPred		0.084	T
GERP RS		6.0
Varity_R		0.87
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2228605; hg19: chr1-109884672; COSMIC: COSV99860517;