14-30630553-T-C

Position:

• chr14-30630553-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• Conservation: PhyloP100: 7.56

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
SCFD1	NM_016106.4	c.209T>C	p.Ile70Thr	missense_variant	3/25	ENST00000458591.7	NP_057190.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCFD1	ENST00000458591.7	c.209T>C	p.Ile70Thr	missense_variant	3/25	1	NM_016106.4	ENSP00000390783.2

Frequencies

GnomAD3 genomes AF: 0.00324 AC: 493 AN: 152186 Hom.: 2 Cov.: 32

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

GnomAD3 exomes AF: 0.00330 AC: 827 AN: 250812 Hom.: 3 AF XY: 0.00334 AC XY: 453 AN XY: 135580

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 SAS exome AF: 0.00216

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.: 17 Cov.: 25 AF XY: 0.00324 AC XY: 2301 AN XY: 709872

Gnomad4 AFR exome AF: 0.000533

Gnomad4 AMR exome AF: 0.00499

Gnomad4 ASJ exome AF: 0.000426

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00204

Gnomad4 FIN exome AF: 0.00443

Gnomad4 NFE exome AF: 0.00348

Gnomad4 OTH exome AF: 0.00290

GnomAD4 genome AF: 0.00324 AC: 493 AN: 152304 Hom.: 2 Cov.: 32 AF XY: 0.00320 AC XY: 238 AN XY: 74468

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.00824

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00349

Gnomad4 NFE AF: 0.00418

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00360 Hom.: 1

Bravo AF: 0.00349

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00523 AC: 45

ExAC AF: 0.00329 AC: 399

Asia WGS AF: 0.000868 AC: 3 AN: 3472

EpiCase AF: 0.00294

EpiControl AF: 0.00279

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

UM ALS/MND Lab, University Of Malta

Jul 31, 2020

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

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

SCFD1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 21, 2022

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	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.021	T;T;T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.8	L;.;.
PrimateAI	Pathogenic	0.88	D
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	T
GERP RS		5.6
Varity_R		0.54
gMVP		0.77

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

LitVar

Other links and lift over

dbSNP: rs61754480; hg19: chr14-31099759;