Variant 6-70477330-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001162529.3(FAM135A):c.540A>G(p.Ile180Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000256 in 1,611,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

FAM135A
NM_001162529.3 missense, splice_region

Scores

Splicing: ADA: 0.006268

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.97

Variant links:

Genes affected

FAM135A (HGNC:21084): (family with sequence similarity 135 member A) Predicted to be involved in cellular lipid metabolic process. [provided by Alliance of Genome Resources, Apr 2022]

FAM135A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25373673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM135A	NM_001162529.3 linkuse as main transcript	c.540A>G	p.Ile180Met	missense_variant, splice_region_variant	8/22	ENST00000418814.7	NP_001156001.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM135A	ENST00000418814.7 linkuse as main transcript	c.540A>G	p.Ile180Met	missense_variant, splice_region_variant	8/22	5	NM_001162529.3	ENSP00000410768	A1	Q9P2D6-1

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

152124

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000249

AC:

AN:

249086

Hom.:

AF XY:

0.000245

AC XY:

AN XY:

134586

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000200

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.000479

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000259

AC:

378

AN:

1459802

Hom.:

Cov.:

AF XY:

0.000281

AC XY:

204

AN XY:

726094

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000768

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000317

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000224

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000534

Hom.:

Bravo

AF:

0.000174

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000297

AC:

EpiCase

AF:

0.000657

EpiControl

AF:

0.000535

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2023

The c.540A>G (p.I180M) alteration is located in exon 6 (coding exon 5) of the FAM135A gene. This alteration results from a A to G substitution at nucleotide position 540, causing the isoleucine (I) at amino acid position 180 to be replaced by a methionine (M). 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

0.39

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;T;.;.;.;T;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

.;D;D;D;D;D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.25

T;T;T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.8

M;.;.;.;M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D;N

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.4

N;N;N;N;N;.;N

REVEL

Benign

0.24

Sift

Benign

0.039

D;T;T;D;D;.;D

Sift4G

Uncertain

0.0020

D;D;T;D;D;D;D

Polyphen

1.0

D;.;P;D;D;D;D

Vest4

0.81

MVP

0.38

MPC

0.73

ClinPred

0.61

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.45

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0063

dbscSNV1_RF

Benign

0.070

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

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