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GeneBe

19-5653163-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001201338.2(SAFB):c.1342T>C(p.Cys448Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SAFB
NM_001201338.2 missense

Scores

9
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.90
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.939

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SAFBNM_001201338.2 linkuse as main transcriptc.1342T>C p.Cys448Arg missense_variant 10/21 ENST00000588852.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SAFBENST00000588852.2 linkuse as main transcriptc.1342T>C p.Cys448Arg missense_variant 10/211 NM_001201338.2 P5Q15424-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461884
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727242
show subpopulations
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 04, 2024The c.1342T>C (p.C448R) alteration is located in exon 10 (coding exon 10) of the SAFB gene. This alteration results from a T to C substitution at nucleotide position 1342, causing the cysteine (C) at amino acid position 448 to be replaced by an arginine (R). 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
1.0
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
30
DANN
Uncertain
0.99
DEOGEN2
Benign
0.41
T;.;.;.
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.97
D;D;D;D
M_CAP
Pathogenic
0.44
D
MetaRNN
Pathogenic
0.94
D;D;D;D
MetaSVM
Uncertain
0.040
D
MutationAssessor
Benign
1.1
L;L;.;L
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-11
D;.;D;.
REVEL
Pathogenic
0.87
Sift
Uncertain
0.0010
D;.;D;.
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
0.99
D;.;.;.
Vest4
0.92
MutPred
0.74
Gain of MoRF binding (P = 0.0174);Gain of MoRF binding (P = 0.0174);.;Gain of MoRF binding (P = 0.0174);
MVP
0.87
MPC
2.5
ClinPred
1.0
D
GERP RS
4.8
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.7
Varity_R
0.95
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1327616151; hg19: chr19-5653174; API