19-5587311-G-A

Variant names:

• chr19-5587311-G-A
• rs760276209
• NM_014649.3:c.2794C>T

Variant summary

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

The NM_014649.3(SAFB2):​c.2794C>T​(p.Arg932Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,612,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. R932L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: SAFB2 NM_014649.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.390
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23460215).
• BS2: High AC in GnomAdExome4 at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAFB2	NM_014649.3	c.2794C>T	p.Arg932Trp	missense_variant	Exon 21 of 21	ENST00000252542.9	NP_055464.1
SAFB2	XM_011528449.4	c.*90C>T		3_prime_UTR_variant	Exon 21 of 21		XP_011526751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAFB2	ENST00000252542.9	c.2794C>T	p.Arg932Trp	missense_variant	Exon 21 of 21	1	NM_014649.3	ENSP00000252542.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.0000122 AC: 3 AN: 246612 AF XY: 0.00000748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000329 AC: 48 AN: 1460222 Hom.: 0 Cov.: 33 AF XY: 0.0000275 AC XY: 20 AN XY: 726312

African (AFR) AF: 0.0000299 AC: 1 AN: 33454

American (AMR) AF: 0.0000225 AC: 1 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1111486

Other (OTH) AF: 0.0000166 AC: 1 AN: 60314

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152036 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74276

African (AFR) AF: 0.0000724 AC: 3 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2794C>T (p.R932W) alteration is located in exon 21 (coding exon 21) of the SAFB2 gene. This alteration results from a C to T substitution at nucleotide position 2794, causing the arginine (R) at amino acid position 932 to be replaced by a tryptophan (W). 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	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.39
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.0070	B
Vest4		0.62
MutPred		0.18		Loss of catalytic residue at R932 (P = 0.0556);
MVP		0.18
MPC		0.16
ClinPred		0.95	D
GERP RS		1.8
Varity_R		0.19
gMVP		0.10
Mutation Taster		=94/6	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: rs760276209; hg19: chr19-5587322;