19-5654392-T-C

Position:

• chr19-5654392-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001201338.2(SAFB):​c.1691T>C​(p.Val564Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SAFB NM_001201338.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50

Genes affected

SAFB (HGNC:10520): (scaffold attachment factor B) This gene encodes a DNA-binding protein which has high specificity for scaffold or matrix attachment region DNA elements (S/MAR DNA). This protein is thought to be involved in attaching the base of chromatin loops to the nuclear matrix but there is conflicting evidence as to whether this protein is a component of chromatin or a nuclear matrix protein. Scaffold attachment factors are a specific subset of nuclear matrix proteins (NMP) that specifically bind to S/MAR. The encoded protein is thought to serve as a molecular base to assemble a 'transcriptosome complex' in the vicinity of actively transcribed genes. It is involved in the regulation of heat shock protein 27 transcription, can act as an estrogen receptor co-repressor and is a candidate for breast tumorigenesis. This gene is arranged head-to-head with a similar gene whose product has the same functions. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAFB	NM_001201338.2	c.1691T>C	p.Val564Ala	missense_variant	13/21	ENST00000588852.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAFB	ENST00000588852.2	c.1691T>C	p.Val564Ala	missense_variant	13/21	1	NM_001201338.2	P5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2024

The c.1691T>C (p.V564A) alteration is located in exon 13 (coding exon 13) of the SAFB gene. This alteration results from a T to C substitution at nucleotide position 1691, causing the valine (V) at amino acid position 564 to be replaced by an alanine (A). 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	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;.;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.55	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.0	D;.;D;.
REVEL	Uncertain	0.33
Sift	Benign	0.034	D;.;D;.
Sift4G	Benign	0.073	T;T;T;T
Polyphen		1.0	D;.;.;.
Vest4		0.61
MutPred		0.23		Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);.;Gain of sheet (P = 0.0073);
MVP		0.49
MPC		2.1
ClinPred		0.97	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-5654403;