chr21-31671619-G-T

Variant names:

• chr21-31671619-G-T
• NM_020706.2:c.3224C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020706.2(SCAF4):​c.3224C>A​(p.Ala1075Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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)
• Consequence: SCAF4 NM_020706.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.666
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0261285).

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.3224C>A	p.Ala1075Asp	missense	Exon 20 of 20	NP_065757.1	O95104-1
	SCAF4	NM_001145444.1		c.3179C>A	p.Ala1060Asp	missense	Exon 19 of 19	NP_001138916.1	O95104-3
	SCAF4	NM_001145445.1		c.3158C>A	p.Ala1053Asp	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.3224C>A	p.Ala1075Asp	missense	Exon 20 of 20	ENSP00000286835.7	O95104-1
	SCAF4	ENST00000434667.3	TSL:1	c.3179C>A	p.Ala1060Asp	missense	Exon 19 of 19	ENSP00000402377.2	O95104-3
	SCAF4	ENST00000399804.5	TSL:1	c.3158C>A	p.Ala1053Asp	missense	Exon 20 of 20	ENSP00000382703.1	O95104-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	3.9
DANN	Benign	0.88
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.67
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.040
Sift	Benign	0.044	D
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.083		Loss of MoRF binding (P = 0.0286)
MVP		0.19
MPC		0.35
ClinPred		0.14	T
GERP RS		-6.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.093
gMVP		0.012
Mutation Taster		=94/6	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

hg19: chr21-33043932;