21-31671667-C-T

Variant names:

• chr21-31671667-C-T
• rs753234671
• NM_020706.2:c.3176G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020706.2(SCAF4):​c.3176G>A​(p.Arg1059Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R1059T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCAF4 NM_020706.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.07
• Publications: 0 publications found

Genes affected

SCAF4 (HGNC:19304): (SR-related CTD associated factor 4) This gene likely encodes a member of the arginine/serine-rich splicing factor family. A similar protein in Rat appears to bind the large subunit of RNA polymerase II and provide a link between transcription and pre-mRNA splicing. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2009]

SCAF4 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Franklin by Genoox, Ambry Genetics, ClinGen
• Fliedner-Zweier syndrome

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28249484).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020706.2. 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
	SCAF4	NM_020706.2	MANE Select	c.3176G>A	p.Arg1059Lys	missense	Exon 20 of 20	NP_065757.1	O95104-1
	SCAF4	NM_001145444.1		c.3131G>A	p.Arg1044Lys	missense	Exon 19 of 19	NP_001138916.1	O95104-3
	SCAF4	NM_001145445.1		c.3110G>A	p.Arg1037Lys	missense	Exon 20 of 20	NP_001138917.1	O95104-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCAF4	ENST00000286835.12	TSL:1 MANE Select	c.3176G>A	p.Arg1059Lys	missense	Exon 20 of 20	ENSP00000286835.7	O95104-1
	SCAF4	ENST00000434667.3	TSL:1	c.3131G>A	p.Arg1044Lys	missense	Exon 19 of 19	ENSP00000402377.2	O95104-3
	SCAF4	ENST00000399804.5	TSL:1	c.3110G>A	p.Arg1037Lys	missense	Exon 20 of 20	ENSP00000382703.1	O95104-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461656 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727142

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111826

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	T
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.043	D
Polyphen		0.98	D
Vest4		0.43
MutPred		0.21		Gain of solvent accessibility (P = 0.0137)
MVP		0.50
MPC		0.24
ClinPred		0.91	D
GERP RS		5.9
Varity_R		0.57
gMVP		0.082
Mutation Taster		=78/22	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: rs753234671; hg19: chr21-33043980;