14-30705839-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016106.4(SCFD1):c.1507G>A(p.Ala503Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCFD1 NM_016106.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27555993).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCFD1	NM_016106.4	c.1507G>A	p.Ala503Thr	missense_variant	18/25	ENST00000458591.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCFD1	ENST00000458591.7	c.1507G>A	p.Ala503Thr	missense_variant	18/25	1	NM_016106.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461300 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726962

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2022

The c.1507G>A (p.A503T) alteration is located in exon 18 (coding exon 18) of the SCFD1 gene. This alteration results from a G to A substitution at nucleotide position 1507, causing the alanine (A) at amino acid position 503 to be replaced by a threonine (T). 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	Benign	0.098
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	23
Dann	Benign	0.39
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.74	N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.17	N;N;N
REVEL	Benign	0.23
Sift	Benign	0.73	T;T;T
Sift4G	Benign	0.69	T;T;T
Polyphen		0.043	B;.;.
Vest4		0.54
MVP		0.33
MPC		0.36
ClinPred		0.77	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.52

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: rs375686488; hg19: chr14-31175045;