19-49646724-C-A

Variant names:

• chr19-49646724-C-A
• rs2081057709
• NM_021228.3:c.372C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021228.3(SCAF1):​c.372C>A​(p.Asp124Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 6.8e-7 (0 hom.)
• Consequence: SCAF1 NM_021228.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

Genes affected

SCAF1 (HGNC:30403): (SR-related CTD associated factor 1) Enables RNA polymerase II C-terminal domain binding activity. Predicted to be involved in RNA splicing; mRNA processing; and transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0996196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCAF1	NM_021228.3	c.372C>A	p.Asp124Glu	missense_variant	Exon 6 of 11	ENST00000360565.8	NP_067051.2
SCAF1	XM_011527194.4	c.381C>A	p.Asp127Glu	missense_variant	Exon 6 of 11		XP_011525496.1
SCAF1	XM_005259122.6	c.372C>A	p.Asp124Glu	missense_variant	Exon 6 of 11		XP_005259179.1
SCAF1	XM_017027083.3	c.102C>A	p.Asp34Glu	missense_variant	Exon 3 of 8		XP_016882572.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCAF1	ENST00000360565.8	c.372C>A	p.Asp124Glu	missense_variant	Exon 6 of 11	2	NM_021228.3	ENSP00000353769.2
SCAF1	ENST00000598359.5	c.372C>A	p.Asp124Glu	missense_variant	Exon 6 of 7	3		ENSP00000473210.1
SCAF1	ENST00000595242.3	c.*105C>A		downstream_gene_variant		3		ENSP00000472276.1
SCAF1	ENST00000601038.5	c.*166C>A		downstream_gene_variant		3		ENSP00000472649.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461662 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727150

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.372C>A (p.D124E) alteration is located in exon 6 (coding exon 5) of the SCAF1 gene. This alteration results from a C to A substitution at nucleotide position 372, causing the aspartic acid (D) at amino acid position 124 to be replaced by a glutamic acid (E). 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	0.32
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.026	T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.95	N;.
REVEL	Benign	0.055
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.58	T;T
Polyphen		0.0060	B;.
Vest4		0.20
MutPred		0.24		Gain of glycosylation at P119 (P = 0.2038);Gain of glycosylation at P119 (P = 0.2038);
MVP		0.043
MPC		0.59
ClinPred		0.47	T
GERP RS		1.1
Varity_R		0.14
gMVP		0.18

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: rs2081057709; hg19: chr19-50149981;