rs758295971

Variant names:

• chr21-31671689-G-A
• rs758295971
• NM_020706.2:c.3154C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-31671689-G-A
• chr21-31671689-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_020706.2(SCAF4):​c.3154C>T​(p.Arg1052Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,520 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: SCAF4 NM_020706.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.89
• 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 -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 12 AD gene.

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.3154C>T	p.Arg1052Cys	missense	Exon 20 of 20	NP_065757.1	O95104-1
	SCAF4	NM_001145444.1		c.3109C>T	p.Arg1037Cys	missense	Exon 19 of 19	NP_001138916.1	O95104-3
	SCAF4	NM_001145445.1		c.3088C>T	p.Arg1030Cys	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.3154C>T	p.Arg1052Cys	missense	Exon 20 of 20	ENSP00000286835.7	O95104-1
	SCAF4	ENST00000434667.3	TSL:1	c.3109C>T	p.Arg1037Cys	missense	Exon 19 of 19	ENSP00000402377.2	O95104-3
	SCAF4	ENST00000399804.5	TSL:1	c.3088C>T	p.Arg1030Cys	missense	Exon 20 of 20	ENSP00000382703.1	O95104-2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152018 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251462 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461502 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727070

African (AFR) AF: 0.0000598 AC: 2 AN: 33470

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

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

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111670

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152018 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74236

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41382

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.9
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.57
MutPred		0.25		Loss of MoRF binding (P = 0.0548)
MVP		0.74
MPC		0.32
ClinPred		0.79	D
GERP RS		5.9
Varity_R		0.26
gMVP		0.046
Mutation Taster		=76/24	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: rs758295971; hg19: chr21-33044002;