21-31671714-G-C

Variant names:

• chr21-31671714-G-C
• rs2049701786
• NM_020706.2:c.3129C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020706.2(SCAF4):​c.3129C>G​(p.His1043Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,824 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCAF4 NM_020706.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30189973).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCAF4	NM_020706.2	c.3129C>G	p.His1043Gln	missense_variant	Exon 20 of 20	ENST00000286835.12	NP_065757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCAF4	ENST00000286835.12	c.3129C>G	p.His1043Gln	missense_variant	Exon 20 of 20	1	NM_020706.2	ENSP00000286835.7
SCAF4	ENST00000434667.3	c.3084C>G	p.His1028Gln	missense_variant	Exon 19 of 19	1		ENSP00000402377.2
SCAF4	ENST00000399804.5	c.3063C>G	p.His1021Gln	missense_variant	Exon 20 of 20	1		ENSP00000382703.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461824 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3129C>G (p.H1043Q) alteration is located in exon 20 (coding exon 20) of the SCAF4 gene. This alteration results from a C to G substitution at nucleotide position 3129, causing the histidine (H) at amino acid position 1043 to be replaced by a glutamine (Q). 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	0.18
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D;D;D
Sift4G	Benign	0.32	T;T;T
Polyphen		1.0	D;B;.
Vest4		0.45
MutPred		0.25		Gain of helix (P = 0.132);.;.;
MVP		0.55
MPC		0.24
ClinPred		0.90	D
GERP RS		5.0
Varity_R		0.49
gMVP		0.067

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

Publications

LitVar

Other links and lift over

dbSNP: rs2049701786; hg19: chr21-33044027;