19-5654435-A-C

Position:

• chr19-5654435-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001201338.2(SAFB):​c.1734A>C​(p.Lys578Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SAFB NM_001201338.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.300

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 3 ACMG points.

• PM1: In a cross_link Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2); alternate (size 0) in uniprot entity SAFB1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2680149).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAFB	NM_001201338.2	c.1734A>C	p.Lys578Asn	missense_variant	13/21	ENST00000588852.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAFB	ENST00000588852.2	c.1734A>C	p.Lys578Asn	missense_variant	13/21	1	NM_001201338.2	P5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.88e-7 AC: 1 AN: 1453408 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 723530

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

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

Nov 12, 2021

The c.1734A>C (p.K578N) alteration is located in exon 13 (coding exon 13) of the SAFB gene. This alteration results from a A to C substitution at nucleotide position 1734, causing the lysine (K) at amino acid position 578 to be replaced by an asparagine (N). 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	0.96
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;.;.;.
Eigen	Benign	0.080
Eigen_PC	Benign	-0.069
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.4	D;.;D;.
REVEL	Benign	0.12
Sift	Uncertain	0.019	D;.;D;.
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.99	D;.;.;.
Vest4		0.46
MutPred		0.39		Loss of methylation at K578 (P = 0.0015);Loss of methylation at K578 (P = 0.0015);.;Loss of methylation at K578 (P = 0.0015);
MVP		0.43
MPC		2.0
ClinPred		0.98	D
GERP RS		0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-5654446;