19-5587702-C-A

Variant names:

• chr19-5587702-C-A
• rs565231015
• NM_014649.3:c.2704G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014649.3(SAFB2):​c.2704G>T​(p.Gly902Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000715 in 1,398,260 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SAFB2 NM_014649.3 missense, splice_region
• Scores: Splicing: ADA: 0.1239
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.93
• Publications: 1 publications found

Genes affected

SAFB2 (HGNC:21605): (scaffold attachment factor B2) The protein encoded by this gene, along with its paralog (scaffold attachment factor B1), is a repressor of estrogen receptor alpha. The encoded protein binds scaffold/matrix attachment region (S/MAR) DNA and is involved in cell cycle regulation, apoptosis, differentiation, the stress response, and regulation of immune genes. [provided by RefSeq, May 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014649.3. 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
	SAFB2	NM_014649.3	MANE Select	c.2704G>T	p.Gly902Trp	missense splice_region	Exon 20 of 21	NP_055464.1	Q14151-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAFB2	ENST00000252542.9	TSL:1 MANE Select	c.2704G>T	p.Gly902Trp	missense splice_region	Exon 20 of 21	ENSP00000252542.3	Q14151-1
	SAFB2	ENST00000912090.1		c.2722G>T	p.Gly908Trp	missense splice_region	Exon 20 of 21	ENSP00000582149.1
	SAFB2	ENST00000850599.1		c.2704G>T	p.Gly902Trp	missense splice_region	Exon 20 of 21	ENSP00000520886.1	Q14151-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000129 AC: 2 AN: 155286 AF XY: 0.0000122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000179

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398260 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 689652

African (AFR) AF: 0.00 AC: 0 AN: 31524

American (AMR) AF: 0.00 AC: 0 AN: 35510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25106

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35726

South Asian (SAS) AF: 0.00 AC: 0 AN: 79080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49050

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078632

Other (OTH) AF: 0.00 AC: 0 AN: 57942

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000656 AC: 1 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74518

⚠️ 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: 41600

American (AMR) AF: 0.00 AC: 0 AN: 15312

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

⚠️ 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: 0.00000378

ExAC AF: 0.0000105 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.46		Loss of methylation at R903 (P = 0.0232)
MVP		0.25
MPC		0.25
ClinPred		0.97	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.26
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.12
dbscSNV1_RF	Benign	0.38
SpliceAI score (max)		0.10		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: rs565231015; hg19: chr19-5587713;