19-49646149-A-G

Variant names:

• chr19-49646149-A-G
• rs374115603
• NM_021228.3:c.208A>G

Variant summary

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

The NM_021228.3(SCAF1):​c.208A>G​(p.Ser70Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,611,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SCAF1 NM_021228.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74

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=0.19502413).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCAF1	NM_021228.3	c.208A>G	p.Ser70Gly	missense_variant	Exon 4 of 11	ENST00000360565.8	NP_067051.2
SCAF1	XM_011527194.4	c.217A>G	p.Ser73Gly	missense_variant	Exon 4 of 11		XP_011525496.1
SCAF1	XM_005259122.6	c.208A>G	p.Ser70Gly	missense_variant	Exon 4 of 11		XP_005259179.1
SCAF1	XM_017027083.3	c.-95A>G		5_prime_UTR_variant	Exon 1 of 8		XP_016882572.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCAF1	ENST00000360565.8	c.208A>G	p.Ser70Gly	missense_variant	Exon 4 of 11	2	NM_021228.3	ENSP00000353769.2
SCAF1	ENST00000598359.5	c.208A>G	p.Ser70Gly	missense_variant	Exon 4 of 7	3		ENSP00000473210.1
SCAF1	ENST00000595242.3	c.208A>G	p.Ser70Gly	missense_variant	Exon 3 of 4	3		ENSP00000472276.1
SCAF1	ENST00000601038.5	c.208A>G	p.Ser70Gly	missense_variant	Exon 3 of 4	3		ENSP00000472649.1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151580 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000801 AC: 2 AN: 249822 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135136

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1459636 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 726204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151580 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73994

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.208A>G (p.S70G) alteration is located in exon 4 (coding exon 3) of the SCAF1 gene. This alteration results from a A to G substitution at nucleotide position 208, causing the serine (S) at amino acid position 70 to be replaced by a glycine (G). 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	0.21
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Benign	0.86
DEOGEN2	Benign	0.060	T;T;T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.59	T;T;T;T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.8	N;.;.;.
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.97	D;.;.;.
Vest4		0.65
MutPred		0.19		Loss of phosphorylation at S70 (P = 0.0019);Loss of phosphorylation at S70 (P = 0.0019);Loss of phosphorylation at S70 (P = 0.0019);Loss of phosphorylation at S70 (P = 0.0019);
MVP		0.43
MPC		0.58
ClinPred		0.55	D
GERP RS		4.2
Varity_R		0.32
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs374115603; hg19: chr19-50149406;