chr19-5641912-T-G

Variant names:

• chr19-5641912-T-G
• rs754338398
• NM_001201338.2:c.512T>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001201338.2(SAFB):​c.512T>G​(p.Met171Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,878 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SAFB NM_001201338.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.89
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32684022).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001201338.2. 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
	SAFB	NM_001201338.2	MANE Select	c.512T>G	p.Met171Arg	missense	Exon 4 of 21	NP_001188267.1	Q15424-3
	SAFB	NM_001201339.2		c.512T>G	p.Met171Arg	missense	Exon 4 of 21	NP_001188268.1	Q15424-4
	SAFB	NM_002967.4		c.512T>G	p.Met171Arg	missense	Exon 4 of 21	NP_002958.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAFB	ENST00000588852.2	TSL:1 MANE Select	c.512T>G	p.Met171Arg	missense	Exon 4 of 21	ENSP00000467423.1	Q15424-3
	SAFB	ENST00000592224.5	TSL:1	c.512T>G	p.Met171Arg	missense	Exon 4 of 21	ENSP00000464840.1	Q15424-4
	SAFB	ENST00000292123.9	TSL:1	c.512T>G	p.Met171Arg	missense	Exon 4 of 21	ENSP00000292123.4	Q15424-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251464 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000247 AC: 3

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	Benign	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.21
Sift	Benign	0.23	T
Sift4G	Benign	0.53	T
Polyphen		0.90	P
Vest4		0.63
MVP		0.51
MPC		0.23
ClinPred		0.13	T
GERP RS		1.1
Varity_R		0.32
gMVP		0.25
Mutation Taster		=29/171	disease causing

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: rs754338398; hg19: chr19-5641923;