chr12-49598909-G-A

Variant names:

• chr12-49598909-G-A
• rs78475684
• NM_032130.3:c.2210C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032130.3(FAM186B):​c.2210C>T​(p.Thr737Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,613,688 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (57 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (77 hom.)
• Consequence: FAM186B NM_032130.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.461
• Publications: 7 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030552745).
• BP6: Variant 12-49598909-G-A is Benign according to our data. Variant chr12-49598909-G-A is described in ClinVar as Benign. ClinVar VariationId is 713126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0514 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032130.3. 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
	FAM186B	NM_032130.3	MANE Select	c.2210C>T	p.Thr737Met	missense	Exon 5 of 7	NP_115506.1	Q8IYM0-1
	FAM186B	NR_027450.2		n.2552C>T		non_coding_transcript_exon	Exon 5 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM186B	ENST00000257894.2	TSL:1 MANE Select	c.2210C>T	p.Thr737Met	missense	Exon 5 of 7	ENSP00000257894.2	Q8IYM0-1
	FAM186B	ENST00000532262.5	TSL:1	c.1049C>T	p.Thr350Met	missense	Exon 2 of 5	ENSP00000436995.1	A0A0C4DGG0
	FAM186B	ENST00000551047.5	TSL:5	c.633+2098C>T		intron	N/A	ENSP00000448656.1	F8VRJ5

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2354 AN: 151684 Hom.: 57 Cov.: 31

Gnomad AFR AF: 0.0531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00756

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.00209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00439 AC: 1103 AN: 251456 AF XY: 0.00333

Gnomad AFR exome AF: 0.0547

Gnomad AMR exome AF: 0.00379

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00170 AC: 2487 AN: 1461884 Hom.: 77 Cov.: 31 AF XY: 0.00155 AC XY: 1129 AN XY: 727244

African (AFR) AF: 0.0559 AC: 1873 AN: 33478

American (AMR) AF: 0.00378 AC: 169 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00119 AC: 103 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.0000800 AC: 89 AN: 1112010

Other (OTH) AF: 0.00371 AC: 224 AN: 60394

GnomAD4 genome AF: 0.0156 AC: 2366 AN: 151804 Hom.: 57 Cov.: 31 AF XY: 0.0154 AC XY: 1141 AN XY: 74182

African (AFR) AF: 0.0532 AC: 2200 AN: 41338

American (AMR) AF: 0.00755 AC: 115 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000391 AC: 2 AN: 5120

South Asian (SAS) AF: 0.00209 AC: 10 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67964

Other (OTH) AF: 0.0114 AC: 24 AN: 2106

Alfa AF: 0.00606 Hom.: 45

Bravo AF: 0.0180

ESP6500AA AF: 0.0606 AC: 267

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00549 AC: 666

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.46
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Benign	0.041
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.88	P
Vest4		0.27
MVP		0.099
MPC		0.29
ClinPred		0.026	T
GERP RS		2.3
PromoterAI		0.041	Neutral
Varity_R		0.040
gMVP		0.16
Mutation Taster		=100/0	polymorphism

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: rs78475684; hg19: chr12-49992692;