19-5587948-C-T

Variant names:

• chr19-5587948-C-T
• rs772496640
• NM_014649.3:c.2558G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_014649.3(SAFB2):​c.2558G>A​(p.Arg853Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,858 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SAFB2 NM_014649.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47
• Publications: 0 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06472257).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAFB2	NM_014649.3	c.2558G>A	p.Arg853Gln	missense_variant	Exon 19 of 21	ENST00000252542.9	NP_055464.1
SAFB2	XM_011528449.4	c.2558G>A	p.Arg853Gln	missense_variant	Exon 19 of 21		XP_011526751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAFB2	ENST00000252542.9	c.2558G>A	p.Arg853Gln	missense_variant	Exon 19 of 21	1	NM_014649.3	ENSP00000252542.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152240 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: 0.000192

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: 0.00000814 AC: 2 AN: 245786 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000551

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000906

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460618 Hom.: 0 Cov.: 33 AF XY: 0.00000826 AC XY: 6 AN XY: 726596

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52480

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

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111864

Other (OTH) AF: 0.0000166 AC: 1 AN: 60364

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000659 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2558G>A (p.R853Q) alteration is located in exon 19 (coding exon 19) of the SAFB2 gene. This alteration results from a G to A substitution at nucleotide position 2558, causing the arginine (R) at amino acid position 853 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	0.081
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.021
Sift	Benign	0.13	T
Sift4G	Benign	0.12	T
Polyphen		0.052	B
Vest4		0.25
MVP		0.12
MPC		0.14
ClinPred		0.38	T
GERP RS		3.3
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.9
Varity_R		0.024
gMVP		0.082
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs772496640; hg19: chr19-5587959;