20-43460202-G-A

Variant names:

• chr20-43460202-G-A
• rs147863077
• NM_006275.6:c.551G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006275.6(SRSF6):​c.551G>A​(p.Arg184His) variant causes a missense change. The variant allele was found at a frequency of 0.000334 in 1,613,810 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R184C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: SRSF6 NM_006275.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09

Genes affected

SRSF6 (HGNC:10788): (serine and arginine rich splicing factor 6) The protein encoded by this gene is involved in mRNA splicing and may play a role in the determination of alternative splicing. The encoded nuclear protein belongs to the splicing factor SR family and has been shown to bind with and modulate another member of the family, SFRS12. Alternative splicing results in multiple transcript variants. In addition, two pseudogenes, one on chromosome 17 and the other on the X chromosome, have been found for this gene.[provided by RefSeq, Sep 2010]

ENSG00000288000 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15403196).
• BS2: High AC in GnomAd4 at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRSF6	NM_006275.6	c.551G>A	p.Arg184His	missense_variant	Exon 4 of 6	ENST00000244020.5	NP_006266.2
SRSF6	NR_034009.2	n.957G>A		non_coding_transcript_exon_variant	Exon 5 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRSF6	ENST00000244020.5	c.551G>A	p.Arg184His	missense_variant	Exon 4 of 6	1	NM_006275.6	ENSP00000244020.3
ENSG00000288000	ENST00000657241.1	c.530G>A	p.Arg177His	missense_variant	Exon 4 of 26			ENSP00000499734.1

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000189 AC: 47 AN: 249196 AF XY: 0.000192

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000302

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000330 AC: 483 AN: 1461616 Hom.: 0 Cov.: 33 AF XY: 0.000318 AC XY: 231 AN XY: 727112

Gnomad4 AFR exome AF: 0.0000299 AC: 1 AN: 33470

Gnomad4 AMR exome AF: 0.000157 AC: 7 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26134

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39674

Gnomad4 SAS exome AF: 0.000197 AC: 17 AN: 86252

Gnomad4 FIN exome AF: 0.0000375 AC: 2 AN: 53338

Gnomad4 NFE exome AF: 0.000400 AC: 445 AN: 1111894

Gnomad4 Remaining exome AF: 0.000182 AC: 11 AN: 60362

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74348

Gnomad4 AFR AF: 0.000338 AC: 0.00033774 AN: 0.00033774

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000207 AC: 0.000206782 AN: 0.000206782

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000603 AC: 0.000602675 AN: 0.000602675

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000232 Hom.: 0

Bravo AF: 0.000280

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.551G>A (p.R184H) alteration is located in exon 4 (coding exon 4) of the SRSF6 gene. This alteration results from a G to A substitution at nucleotide position 551, causing the arginine (R) at amino acid position 184 to be replaced by a histidine (H). 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	0.33
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.8	L
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.13
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.045	D
Polyphen		0.99	D
Vest4		0.41
MVP		0.21
MPC		0.095
ClinPred		0.057	T
GERP RS		6.0
Varity_R		0.22
gMVP		0.46
Mutation Taster		=85/15	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

Publications

LitVar

Other links and lift over

dbSNP: rs147863077; hg19: chr20-42088842; COSMIC: COSV99719655;