chr12-49588455-G-A

Position:

• chr12-49588455-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_032130.3(FAM186B):​c.2533C>T​(p.Arg845Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,610,608 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (32 hom.)
• Consequence: FAM186B NM_032130.3 missense, splice_region
• Scores: Splicing: ADA: 0.001258
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.333

Genes affected

FAM186B (HGNC:25296): (family with sequence similarity 186 member B) This gene product is a member of the FAM186 family, however, its exact function is not known. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2009]

PRPF40B (HGNC:25031): (pre-mRNA processing factor 40 homolog B) This gene encodes a WW-domain containing protein similar to yeast splicing factor PRP40. This protein has been shown to interact with Huntingtin and methyl CpG binding protein 2 (MeCP2). Alternative splicing results in different transcript variants. [provided by RefSeq, Aug 2014]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029908419).
• BP6: Variant 12-49588455-G-A is Benign according to our data. Variant chr12-49588455-G-A is described in ClinVar as [Benign]. Clinvar id is 1601350.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00119 (181/152318) while in subpopulation EAS AF= 0.0295 (153/5194). AF 95% confidence interval is 0.0257. There are 4 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM186B	NM_032130.3	c.2533C>T	p.Arg845Cys	missense_variant, splice_region_variant	6/7	ENST00000257894.2	NP_115506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM186B	ENST00000257894.2	c.2533C>T	p.Arg845Cys	missense_variant, splice_region_variant	6/7	1	NM_032130.3	ENSP00000257894	P1

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152200 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0294

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00242 AC: 602 AN: 248840 Hom.: 8 AF XY: 0.00219 AC XY: 294 AN XY: 134380

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.0000875

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0315

Gnomad SAS exome AF: 0.000231

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00107 AC: 1562 AN: 1458290 Hom.: 32 Cov.: 31 AF XY: 0.00100 AC XY: 726 AN XY: 724942

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000675

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0334

Gnomad4 SAS exome AF: 0.000268

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.00287

GnomAD4 genome AF: 0.00119 AC: 181 AN: 152318 Hom.: 4 Cov.: 32 AF XY: 0.00119 AC XY: 89 AN XY: 74480

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0295

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00158 Hom.: 5

Bravo AF: 0.00144

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00226 AC: 274

Asia WGS AF: 0.0140 AC: 49 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.95	.;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Pathogenic	-4.4	D;N
REVEL	Benign	0.069
Sift	Benign	0.069	T;T
Sift4G	Uncertain	0.039	D;D
Polyphen		0.010	.;B
Vest4		0.18
MVP		0.048
MPC		0.18
ClinPred		0.019	T
GERP RS		-1.5
Varity_R		0.052
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.050		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: rs76224014; hg19: chr12-49982238; COSMIC: COSV57721730; COSMIC: COSV57721730;