chr14-30673258-C-A

Variant names:

• chr14-30673258-C-A
• rs1216324528
• NM_016106.4:c.997C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016106.4(SCFD1):​c.997C>A​(p.Pro333Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000704 in 1,420,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P333A) 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, splice_region
• Scores: Splicing: ADA: 0.9904
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.88
• 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]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016106.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCFD1	NM_016106.4	MANE Select	c.997C>A	p.Pro333Thr	missense splice_region	Exon 12 of 25	NP_057190.2
	SCFD1	NM_001283032.1		c.820C>A	p.Pro274Thr	missense splice_region	Exon 11 of 24	NP_001269961.1	Q8WVM8
	SCFD1	NM_182835.2		c.796C>A	p.Pro266Thr	missense splice_region	Exon 11 of 24	NP_878255.1	Q8WVM8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCFD1	ENST00000458591.7	TSL:1 MANE Select	c.997C>A	p.Pro333Thr	missense splice_region	Exon 12 of 25	ENSP00000390783.2	Q8WVM8-1
	SCFD1	ENST00000555259.5	TSL:1	n.*556C>A		splice_region non_coding_transcript_exon	Exon 11 of 18	ENSP00000452323.1	G3V5F3
	SCFD1	ENST00000556768.5	TSL:1	n.*467C>A		splice_region non_coding_transcript_exon	Exon 9 of 22	ENSP00000451811.1	G3V4I1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1420890 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 708286

African (AFR) AF: 0.00 AC: 0 AN: 32506

American (AMR) AF: 0.00 AC: 0 AN: 41326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25576

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38870

South Asian (SAS) AF: 0.00 AC: 0 AN: 81500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52814

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5660

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083926

Other (OTH) AF: 0.00 AC: 0 AN: 58712

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		6.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.1	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.54		Gain of phosphorylation at P333 (P = 0.0203)
MVP		0.66
MPC		1.2
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.68
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.78
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

dbSNP: rs1216324528; hg19: chr14-31142464;