11-66340776-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015399.4(BRMS1):c.533C>T(p.Ser178Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000109 in 1,611,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000098 (0 hom.)
• Consequence: BRMS1 NM_015399.4 missense, splice_region
• Scores: Splicing: ADA: 0.9566
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.41

Genes affected

BRMS1 (HGNC:17262): (BRMS1 transcriptional repressor and anoikis regulator) This gene reduces the metastatic potential, but not the tumorogenicity, of human breast cancer and melanoma cell lines. The protein encoded by this gene localizes primarily to the nucleus and is a component of the mSin3a family of histone deacetylase complexes (HDAC). The protein contains two coiled-coil motifs and several imperfect leucine zipper motifs. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12906668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRMS1	NM_015399.4	c.533C>T	p.Ser178Phe	missense_variant, splice_region_variant	6/10	ENST00000359957.8
BRMS1	NM_001024957.2	c.533C>T	p.Ser178Phe	missense_variant, splice_region_variant	6/10
BRMS1	XM_024448425.2	c.533C>T	p.Ser178Phe	missense_variant, splice_region_variant	6/9
BRMS1	XM_024448426.2	c.533C>T	p.Ser178Phe	missense_variant, splice_region_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRMS1	ENST00000359957.8	c.533C>T	p.Ser178Phe	missense_variant, splice_region_variant	6/10	1	NM_015399.4	P1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000250 AC: 62 AN: 247960 Hom.: 0 AF XY: 0.000193 AC XY: 26 AN XY: 134478

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000697

Gnomad ASJ exome AF: 0.00290

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000990

GnomAD4 exome AF: 0.0000980 AC: 143 AN: 1459010 Hom.: 0 Cov.: 33 AF XY: 0.0000909 AC XY: 66 AN XY: 725794

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000627

Gnomad4 ASJ exome AF: 0.00257

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.000266

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74358

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000955

Alfa AF: 0.000189 Hom.: 0

Bravo AF: 0.000219

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000164

EpiControl AF: 0.00

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

Jan 03, 2024

The c.533C>T (p.S178F) alteration is located in exon 6 (coding exon 5) of the BRMS1 gene. This alteration results from a C to T substitution at nucleotide position 533, causing the serine (S) at amino acid position 178 to be replaced by a phenylalanine (F). 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	Uncertain	0.41
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Uncertain	-0.22	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		0.96	D;P;.
Vest4		0.85
MVP		0.62
MPC		0.70
ClinPred		0.15	T
GERP RS		4.9
Varity_R		0.51
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.96
dbscSNV1_RF	Benign	0.52
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

LitVar

Other links and lift over

dbSNP: rs200297342; hg19: chr11-66108247;