Genetic Variant SCFD1:p.Met68Arg (chr14-30630547-T-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_016106.4(SCFD1):c.203T>G(p.Met68Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,434,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M68T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SCFD1
NM_016106.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.56

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCFD1	NM_016106.4 link	c.203T>G	p.Met68Arg	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.203T>G	p.Met68Arg	missense_variant	Exon 3 of 25	1	NM_016106.4	ENSP00000390783.2		Q8WVM8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.97e-7

AC:

AN:

1434726

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715568

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32320

American (AMR)

AF:

0.0000224

AC:

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25924

East Asian (EAS)

AF:

0.00

AC:

AN:

39326

South Asian (SAS)

AF:

0.00

AC:

AN:

85650

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088410

Other (OTH)

AF:

0.00

AC:

AN:

59416

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 16, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.203T>G (p.M68R) alteration is located in exon 3 (coding exon 3) of the SCFD1 gene. This alteration results from a T to G substitution at nucleotide position 203, causing the methionine (M) at amino acid position 68 to be replaced by an arginine (R). 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

0.65

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.47

T;.;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.054

MetaRNN

Uncertain

0.70

D;D;D

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.9

L;.;.

PhyloP100

7.6

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-4.2

D;D;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0010

D;D;T

Sift4G

Benign

0.18

T;D;T

Polyphen

0.53

P;.;.

Vest4

0.74

MutPred

0.52

Loss of stability (P = 0.0444);.;.;

MVP

0.88

MPC

0.74

ClinPred

0.99

GERP RS

5.6

Varity_R

0.87

gMVP

0.82

Mutation Taster

=7/193

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over