19-49646556-G-T

Variant names:

• chr19-49646556-G-T
• rs45513592
• NM_021228.3:c.292G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021228.3(SCAF1):​c.292G>T​(p.Ala98Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,613,980 control chromosomes in the GnomAD database, including 227 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (11 hom., cov: 32)
  • Exomes 𝑓: 0.015 (216 hom.)
• Consequence: SCAF1 NM_021228.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0190
• Publications: 6 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058086216).
• BP6: Variant 19-49646556-G-T is Benign according to our data. Variant chr19-49646556-G-T is described in ClinVar as Benign. ClinVar VariationId is 710946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0145 (21232/1461724) while in subpopulation NFE AF = 0.0177 (19687/1111942). AF 95% confidence interval is 0.0175. There are 216 homozygotes in GnomAdExome4. There are 10118 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021228.3. 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
	SCAF1	NM_021228.3	MANE Select	c.292G>T	p.Ala98Ser	missense	Exon 5 of 11	NP_067051.2	Q9H7N4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCAF1	ENST00000360565.8	TSL:2 MANE Select	c.292G>T	p.Ala98Ser	missense	Exon 5 of 11	ENSP00000353769.2	Q9H7N4
	SCAF1	ENST00000892601.1		c.313G>T	p.Ala105Ser	missense	Exon 4 of 10	ENSP00000562660.1
	SCAF1	ENST00000892599.1		c.292G>T	p.Ala98Ser	missense	Exon 5 of 11	ENSP00000562658.1

Frequencies

GnomAD3 genomes AF: 0.00842 AC: 1281 AN: 152138 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00687

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00528

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00678 AC: 1701 AN: 250900 AF XY: 0.00677

Gnomad AFR exome AF: 0.00223

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00504

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.00751

GnomAD4 exome AF: 0.0145 AC: 21232 AN: 1461724 Hom.: 216 Cov.: 32 AF XY: 0.0139 AC XY: 10118 AN XY: 727182

African (AFR) AF: 0.00242 AC: 81 AN: 33478

American (AMR) AF: 0.00326 AC: 146 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86252

European-Finnish (FIN) AF: 0.00544 AC: 290 AN: 53346

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.0177 AC: 19687 AN: 1111942

Other (OTH) AF: 0.0166 AC: 1002 AN: 60388

GnomAD4 genome AF: 0.00843 AC: 1283 AN: 152256 Hom.: 11 Cov.: 32 AF XY: 0.00758 AC XY: 564 AN XY: 74450

African (AFR) AF: 0.00282 AC: 117 AN: 41540

American (AMR) AF: 0.00686 AC: 105 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00528 AC: 56 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0145 AC: 986 AN: 68006

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.0112 Hom.: 45

Bravo AF: 0.00902

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0184 AC: 71

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0136 AC: 117

ExAC AF: 0.00670 AC: 813

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0137

EpiControl AF: 0.0121

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	4.4
DANN	Benign	0.60
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.019
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.028
Sift	Benign	0.032	D
Sift4G	Benign	0.14	T
Polyphen		0.51	P
Vest4		0.14
MVP		0.093
MPC		0.58
ClinPred		0.0096	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.027
gMVP		0.088
Mutation Taster		=99/1	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

dbSNP: rs45513592; hg19: chr19-50149813;