chr14-30650628-A-G

Variant names:

• chr14-30650628-A-G
• NM_016106.4:c.733A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016106.4(SCFD1):​c.733A>G​(p.Thr245Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000344 in 1,453,494 control chromosomes in the GnomAD database, including 1 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 15/22 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: 0.0000034 (1 hom.)
• Consequence: SCFD1 NM_016106.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.71
• Publications: 0 publications found

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]

ENSG00000301732 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13660455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCFD1	NM_016106.4	c.733A>G	p.Thr245Ala	missense_variant	Exon 9 of 25	ENST00000458591.7	NP_057190.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCFD1	ENST00000458591.7	c.733A>G	p.Thr245Ala	missense_variant	Exon 9 of 25	1	NM_016106.4	ENSP00000390783.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1453494 Hom.: 1 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 723658

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33248

American (AMR) AF: 0.00 AC: 0 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.0000466 AC: 4 AN: 85820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105030

Other (OTH) AF: 0.0000166 AC: 1 AN: 60086

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000034), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.733A>G (p.T245A) alteration is located in exon 9 (coding exon 9) of the SCFD1 gene. This alteration results from a A to G substitution at nucleotide position 733, causing the threonine (T) at amino acid position 245 to be replaced by an alanine (A). 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	0.066
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.40
DEOGEN2	Benign	0.11	T;.;.;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	D;T;D;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.29	N;.;.;.
PhyloP100		3.7
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.13	N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.88	T;T;T;T
Sift4G	Benign	0.76	T;T;T;T
Polyphen		0.0010	B;.;.;.
Vest4		0.17
MutPred		0.34		Loss of phosphorylation at T245 (P = 0.1145);.;.;.;
MVP		0.49
MPC		0.35
ClinPred		0.49	T
GERP RS		4.5
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.027
gMVP		0.37
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

hg19: chr14-31119834;