12-49598939-G-A

Position:

• chr12-49598939-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032130.3(FAM186B):​c.2180C>T​(p.Ala727Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00455 in 1,613,610 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0047 (37 hom.)
• Consequence: FAM186B NM_032130.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.31

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028708577).
• BP6: Variant 12-49598939-G-A is Benign according to our data. Variant chr12-49598939-G-A is described in ClinVar as [Benign]. Clinvar id is 774327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00324 (492/152040) while in subpopulation SAS AF= 0.0186 (89/4790). AF 95% confidence interval is 0.0155. There are 2 homozygotes in gnomad4. There are 268 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM186B	NM_032130.3	c.2180C>T	p.Ala727Val	missense_variant	5/7	ENST00000257894.2	NP_115506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM186B	ENST00000257894.2	c.2180C>T	p.Ala727Val	missense_variant	5/7	1	NM_032130.3	ENSP00000257894	P1

Frequencies

GnomAD3 genomes AF: 0.00323 AC: 490 AN: 151922 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000798

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0181

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00437

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00480 AC: 1206 AN: 251094 Hom.: 7 AF XY: 0.00590 AC XY: 800 AN XY: 135702

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0180

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.00469

Gnomad OTH exome AF: 0.00539

GnomAD4 exome AF: 0.00469 AC: 6852 AN: 1461570 Hom.: 37 Cov.: 32 AF XY: 0.00524 AC XY: 3808 AN XY: 727084

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0197

Gnomad4 FIN exome AF: 0.00214

Gnomad4 NFE exome AF: 0.00417

Gnomad4 OTH exome AF: 0.00474

GnomAD4 genome AF: 0.00324 AC: 492 AN: 152040 Hom.: 2 Cov.: 31 AF XY: 0.00360 AC XY: 268 AN XY: 74344

Gnomad4 AFR AF: 0.000796

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0186

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00437

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00412 Hom.: 5

Bravo AF: 0.00270

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00561 AC: 681

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00433

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.5
DANN	Benign	0.58
DEOGEN2	Benign	0.0039	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00054	N
LIST_S2	Benign	0.52	T;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.1	.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	3.4	N;N
REVEL	Benign	0.048
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.29
MVP		0.014
MPC		0.13
ClinPred		0.0070	T
GERP RS		2.7
Varity_R		0.024
gMVP		0.0065

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

Other links and lift over

dbSNP: rs140003810; hg19: chr12-49992722;