Genetic Variant FAM186A:p.Ile2164Phe (chr12-50350342-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001145475.3(FAM186A):c.6490A>T(p.Ile2164Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,536,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

FAM186A
NM_001145475.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.27

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.055211544).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM186A	NM_001145475.3 link	c.6490A>T	p.Ile2164Phe	missense_variant	Exon 4 of 8	ENST00000327337.6	NP_001138947.1	A6NE01

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FAM186A	ENST00000327337.6 link	c.6490A>T	p.Ile2164Phe	missense_variant	Exon 4 of 8	5	NM_001145475.3	ENSP00000329995.5	A6NE01
FAM186A	ENST00000543111.5 link	c.6490A>T	p.Ile2164Phe	missense_variant	Exon 4 of 8	5		ENSP00000441337.1	F5GYN0
FAM186A	ENST00000543096.5 link	c.523A>T	p.Ile175Phe	missense_variant	Exon 1 of 5	2		ENSP00000443703.1	F5H8C1

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151662

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000554

AC:

AN:

144500

Hom.:

AF XY:

0.0000655

AC XY:

AN XY:

76284

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000660

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000244

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1384656

Hom.:

Cov.:

AF XY:

0.0000132

AC XY:

AN XY:

681578

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000309

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.33e-7

Gnomad4 OTH exome

AF:

0.000104

GnomAD4 genome

AF:

0.0000264

AC:

AN:

151780

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74124

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000774

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ExAC

AF:

0.0000464

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6490A>T (p.I2164F) alteration is located in exon 4 (coding exon 4) of the FAM186A gene. This alteration results from a A to T substitution at nucleotide position 6490, causing the isoleucine (I) at amino acid position 2164 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Benign

0.93

DEOGEN2

Benign

0.011

.;.;T

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.78

T;T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.055

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

.;.;L

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.16

Sift

Benign

0.52

T;T;T

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.56

MutPred

0.24

.;Loss of catalytic residue at I2164 (P = 0.0394);Loss of catalytic residue at I2164 (P = 0.0394);

MVP

0.11

ClinPred

0.20

GERP RS

3.8

Varity_R

0.18

gMVP

0.040

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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