12-50334028-C-T

Variant names:

• chr12-50334028-C-T
• rs6580742
• NM_001145475.3:c.6579G>A

Variant summary

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

The NM_001145475.3(FAM186A):​c.6579G>A​(p.Met2193Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,551,378 control chromosomes in the GnomAD database, including 21,319 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1346 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19973 hom.)
• Consequence: FAM186A NM_001145475.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.618
• Publications: 32 publications found

Genes affected

FAM186A (HGNC:26980): (family with sequence similarity 186 member A)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019448996).
• BP6: Variant 12-50334028-C-T is Benign according to our data. Variant chr12-50334028-C-T is described in ClinVar as Benign. ClinVar VariationId is 1236725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM186A	NM_001145475.3	c.6579G>A	p.Met2193Ile	missense_variant	Exon 5 of 8	ENST00000327337.6	NP_001138947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM186A	ENST00000327337.6	c.6579G>A	p.Met2193Ile	missense_variant	Exon 5 of 8	5	NM_001145475.3	ENSP00000329995.5
FAM186A	ENST00000543111.5	c.6579G>A	p.Met2193Ile	missense_variant	Exon 5 of 8	5		ENSP00000441337.1
FAM186A	ENST00000543096.5	c.612G>A	p.Met204Ile	missense_variant	Exon 2 of 5	2		ENSP00000443703.1
FAM186A	ENST00000539751.1	n.75G>A		non_coding_transcript_exon_variant	Exon 1 of 3	5		ENSP00000437706.1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17412 AN: 152040 Hom.: 1346 Cov.: 32

Gnomad AFR AF: 0.0340

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.0877

Gnomad ASJ AF: 0.0945

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.121

GnomAD2 exomes AF: 0.118 AC: 18538 AN: 156442 AF XY: 0.122

Gnomad AFR exome AF: 0.0283

Gnomad AMR exome AF: 0.0715

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.000459

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.170

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.162 AC: 226920 AN: 1399220 Hom.: 19973 Cov.: 33 AF XY: 0.161 AC XY: 111285 AN XY: 690136

African (AFR) AF: 0.0279 AC: 881 AN: 31594

American (AMR) AF: 0.0751 AC: 2682 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2545 AN: 25182

East Asian (EAS) AF: 0.000224 AC: 8 AN: 35734

South Asian (SAS) AF: 0.107 AC: 8491 AN: 79222

European-Finnish (FIN) AF: 0.144 AC: 7101 AN: 49278

Middle Eastern (MID) AF: 0.101 AC: 575 AN: 5698

European-Non Finnish (NFE) AF: 0.182 AC: 195968 AN: 1078824

Other (OTH) AF: 0.149 AC: 8669 AN: 57994

GnomAD4 genome AF: 0.114 AC: 17405 AN: 152158 Hom.: 1346 Cov.: 32 AF XY: 0.111 AC XY: 8259 AN XY: 74380

African (AFR) AF: 0.0339 AC: 1409 AN: 41534

American (AMR) AF: 0.0876 AC: 1338 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0945 AC: 328 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5190

South Asian (SAS) AF: 0.103 AC: 498 AN: 4820

European-Finnish (FIN) AF: 0.145 AC: 1536 AN: 10570

Middle Eastern (MID) AF: 0.0856 AC: 25 AN: 292

European-Non Finnish (NFE) AF: 0.175 AC: 11925 AN: 67994

Other (OTH) AF: 0.120 AC: 252 AN: 2108

Alfa AF: 0.147 Hom.: 7039

Bravo AF: 0.106

TwinsUK AF: 0.194 AC: 721

ALSPAC AF: 0.191 AC: 735

ESP6500AA AF: 0.0296 AC: 41

ESP6500EA AF: 0.166 AC: 527

ExAC AF: 0.113 AC: 2748

Asia WGS AF: 0.0410 AC: 144 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26553438, 29547645) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.022	.;.;T
Eigen	Benign	0.048
Eigen_PC	Benign	-0.019
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.60	T;T;T
MetaRNN	Benign	0.0019	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	.;.;L
PhyloP100		0.62
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.6	D;N;N
REVEL	Benign	0.15
Sift	Benign	0.031	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0, 0.98	.;D;D
Vest4		0.17
MutPred		0.12		.;Loss of disorder (P = 0.0736);Loss of disorder (P = 0.0736);
ClinPred		0.043	T
GERP RS		3.5
Varity_R		0.26
gMVP		0.075
Mutation Taster		=95/5	polymorphism (auto)

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: rs6580742; hg19: chr12-50727811; COSMIC: COSV59249733;