14-30630553-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_016106.4(SCFD1):c.209T>C(p.Ile70Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00323 in 1,573,924 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0032 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 17 hom. )

Consequence

SCFD1
NM_016106.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2B:1

Conservation

PhyloP100: 7.56

Publications

13 publications found

Variant links:

Genes affected

SCFD1 (HGNC:20726): (sec1 family domain containing 1) Predicted to enable syntaxin binding activity. Involved in negative regulation of autophagosome assembly; regulation of protein transport; and response to toxic substance. Located in cis-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

SCFD1 links:

ENSG00000301732 (HGNC:):

ENSG00000301732 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020704448).

BS2

High AC in GnomAd4 at 493 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCFD1	NM_016106.4 link	c.209T>C	p.Ile70Thr	missense_variant	Exon 3 of 25	ENST00000458591.7	NP_057190.2	Q8WVM8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCFD1	ENST00000458591.7 link	c.209T>C	p.Ile70Thr	missense_variant	Exon 3 of 25	1	NM_016106.4	ENSP00000390783.2		Q8WVM8-1

Frequencies

GnomAD3 genomes

AF:

0.00324

AC:

493

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00825

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00349

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00418

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00330

AC:

827

AN:

250812

AF XY:

0.00334

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.00492

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00403

Gnomad NFE exome

AF:

0.00411

Gnomad OTH exome

AF:

0.00409

GnomAD4 exome

AF:

0.00322

AC:

4584

AN:

1421620

Hom.:

Cov.:

AF XY:

0.00324

AC XY:

2301

AN XY:

709872

show subpopulations

African (AFR)

AF:

0.000533

AC:

AN:

31880

American (AMR)

AF:

0.00499

AC:

222

AN:

44502

Ashkenazi Jewish (ASJ)

AF:

0.000426

AC:

AN:

25838

East Asian (EAS)

AF:

0.00

AC:

AN:

39230

South Asian (SAS)

AF:

0.00204

AC:

174

AN:

85320

European-Finnish (FIN)

AF:

0.00443

AC:

236

AN:

53322

Middle Eastern (MID)

AF:

0.00176

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.00348

AC:

3743

AN:

1076936

Other (OTH)

AF:

0.00290

AC:

171

AN:

58914

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.422

Heterozygous variant carriers

193

386

580

773

966

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00324

AC:

493

AN:

152304

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

238

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000625

AC:

AN:

41578

American (AMR)

AF:

0.00824

AC:

126

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00186

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00349

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00418

AC:

284

AN:

68004

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

102

127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00348

Hom.:

Bravo

AF:

0.00349

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00523

AC:

ExAC

AF:

0.00329

AC:

399

Asia WGS

AF:

0.000868

AC:

AN:

3472

EpiCase

AF:

0.00294

EpiControl

AF:

0.00279

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis

Uncertain:1

Jul 31, 2020

UM ALS/MND Lab, University Of Malta

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:case-control

Frequency of the Ile70Thr variant in the SCFD1 gene is slightly higher for ALS patients (0.004660) compared to controls (0.003843) within the Project MinE ALS case-control cohort. In this context, since the evidence is not strong enough to support causation or genetic risk, the variant has been classified as having uncertain significance. -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

SCFD1-related disorder

Benign:1

Apr 21, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;.;D

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.021

T;T;T

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

1.8

L;.;.

PhyloP100

7.6

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.4

D;D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

0.35

B;.;.

Vest4

0.90

MVP

0.92

MPC

1.1

ClinPred

0.028

GERP RS

5.6

Varity_R

0.54

gMVP

0.77

Mutation Taster

=44/56

disease causing

(source)

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

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14-30630553-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over