Genetic Variant FAM186A:p.Lys187Gln (chr12-50360780-T-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001145475.3(FAM186A):c.559A>C(p.Lys187Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.652 in 1,534,630 control chromosomes in the GnomAD database, including 329,259 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.64 ( 31488 hom., cov: 32)

Exomes 𝑓: 0.65 ( 297771 hom. )

Consequence

FAM186A
NM_001145475.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.20

Variant links:

Genes affected

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

FAM186A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.8962045E-6).

BP6

Variant 12-50360780-T-G is Benign according to our data. Variant chr12-50360780-T-G is described in ClinVar as [Benign]. Clinvar id is 1278322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.72 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM186A	NM_001145475.3 link	c.559A>C	p.Lys187Gln	missense_variant	Exon 3 of 8	ENST00000327337.6	NP_001138947.1	A6NE01

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM186A	ENST00000327337.6 link	c.559A>C	p.Lys187Gln	missense_variant	Exon 3 of 8	5	NM_001145475.3	ENSP00000329995.5		A6NE01
FAM186A	ENST00000543111.5 link	c.559A>C	p.Lys187Gln	missense_variant	Exon 3 of 8	5		ENSP00000441337.1		F5GYN0

Frequencies

GnomAD3 genomes

AF:

0.638

AC:

96788

AN:

151800

Hom.:

31453

Cov.:

show subpopulations

Gnomad AFR

AF:

0.533

Gnomad AMI

AF:

0.774

Gnomad AMR

AF:

0.730

Gnomad ASJ

AF:

0.701

Gnomad EAS

AF:

0.739

Gnomad SAS

AF:

0.508

Gnomad FIN

AF:

0.750

Gnomad MID

AF:

0.639

Gnomad NFE

AF:

0.660

Gnomad OTH

AF:

0.627

GnomAD3 exomes

AF:

0.672

AC:

94656

AN:

140946

Hom.:

32489

AF XY:

0.660

AC XY:

49079

AN XY:

74392

show subpopulations

Gnomad AFR exome

AF:

0.525

Gnomad AMR exome

AF:

0.784

Gnomad ASJ exome

AF:

0.708

Gnomad EAS exome

AF:

0.748

Gnomad SAS exome

AF:

0.516

Gnomad FIN exome

AF:

0.750

Gnomad NFE exome

AF:

0.662

Gnomad OTH exome

AF:

0.658

GnomAD4 exome

AF:

0.653

AC:

903445

AN:

1382710

Hom.:

297771

Cov.:

AF XY:

0.650

AC XY:

442416

AN XY:

681044

show subpopulations

Gnomad4 AFR exome

AF:

0.525

Gnomad4 AMR exome

AF:

0.771

Gnomad4 ASJ exome

AF:

0.704

Gnomad4 EAS exome

AF:

0.754

Gnomad4 SAS exome

AF:

0.521

Gnomad4 FIN exome

AF:

0.740

Gnomad4 NFE exome

AF:

0.655

Gnomad4 OTH exome

AF:

0.639

GnomAD4 genome

AF:

0.638

AC:

96880

AN:

151920

Hom.:

31488

Cov.:

AF XY:

0.643

AC XY:

47773

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.534

Gnomad4 AMR

AF:

0.730

Gnomad4 ASJ

AF:

0.701

Gnomad4 EAS

AF:

0.739

Gnomad4 SAS

AF:

0.509

Gnomad4 FIN

AF:

0.750

Gnomad4 NFE

AF:

0.660

Gnomad4 OTH

AF:

0.628

Alfa

AF:

0.659

Hom.:

81286

Bravo

AF:

0.636

TwinsUK

AF:

0.641

AC:

2375

ALSPAC

AF:

0.645

AC:

2487

ExAC

AF:

0.587

AC:

12416

Asia WGS

AF:

0.609

AC:

2116

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.0045

.;T

Eigen

Benign

-0.074

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.49

T;T

MetaRNN

Benign

0.0000019

T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

0.32

.;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.12

Sift

Benign

0.25

T;T

Sift4G

Uncertain

0.037

D;D

Polyphen

0.99

.;D

Vest4

0.067

ClinPred

0.037

GERP RS

4.7

Varity_R

0.13

gMVP

0.0097

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over