14-30694827-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_016106.4(SCFD1):c.1297A>G(p.Thr433Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0174 in 1,582,258 control chromosomes in the GnomAD database, including 303 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.013 (21 hom., cov: 32)
  • Exomes 𝑓: 0.018 (282 hom.)
• Consequence: SCFD1 NM_016106.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.75

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005932212).
• BP6: Variant 14-30694827-A-G is Benign according to our data. Variant chr14-30694827-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 981027.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0128 (1946/152296) while in subpopulation NFE AF= 0.0195 (1328/68028). AF 95% confidence interval is 0.0186. There are 21 homozygotes in gnomad4. There are 934 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1946 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCFD1	NM_016106.4	c.1297A>G	p.Thr433Ala	missense_variant	15/25	ENST00000458591.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCFD1	ENST00000458591.7	c.1297A>G	p.Thr433Ala	missense_variant	15/25	1	NM_016106.4	A2

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1946 AN: 152178 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0178

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.0128 AC: 2809 AN: 219202 Hom.: 31 AF XY: 0.0131 AC XY: 1556 AN XY: 119078

Gnomad AFR exome AF: 0.00293

Gnomad AMR exome AF: 0.00764

Gnomad ASJ exome AF: 0.00788

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00718

Gnomad FIN exome AF: 0.0119

Gnomad NFE exome AF: 0.0193

Gnomad OTH exome AF: 0.0118

GnomAD4 exome AF: 0.0179 AC: 25601 AN: 1429962 Hom.: 282 Cov.: 31 AF XY: 0.0175 AC XY: 12464 AN XY: 710768

Gnomad4 AFR exome AF: 0.00269

Gnomad4 AMR exome AF: 0.00843

Gnomad4 ASJ exome AF: 0.00808

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00782

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.0207

Gnomad4 OTH exome AF: 0.0158

GnomAD4 genome AF: 0.0128 AC: 1946 AN: 152296 Hom.: 21 Cov.: 32 AF XY: 0.0125 AC XY: 934 AN XY: 74470

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.0178

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00704

Gnomad4 FIN AF: 0.0102

Gnomad4 NFE AF: 0.0195

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0171 Hom.: 19

Bravo AF: 0.0123

TwinsUK AF: 0.0221 AC: 82

ALSPAC AF: 0.0249 AC: 96

ESP6500AA AF: 0.00341 AC: 15

ESP6500EA AF: 0.0204 AC: 175

ExAC AF: 0.0137 AC: 1668

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Amyotrophic lateral sclerosis Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

UM ALS/MND Lab, University Of Malta

Sep 09, 2020

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

SCFD1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	22
Dann	Benign	0.93
DEOGEN2	Benign	0.13	T;.;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;T;T
MetaRNN	Benign	0.0059	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.88	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.93	T;T;T
Polyphen		0.0020	B;.;.
Vest4		0.22
MPC		0.36
ClinPred		0.024	T
GERP RS		4.8
Varity_R		0.071
gMVP		0.44

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: rs61754285; hg19: chr14-31164033; COSMIC: COSV99043732;