Genetic Variant NM_018691.4:c.940A>G (chr5-154011294-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018691.4(FAM114A2):c.940A>G(p.Thr314Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000955 in 1,612,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000098 ( 0 hom. )

Consequence

FAM114A2
NM_018691.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.26

Variant links:

Genes affected

FAM114A2 (HGNC:1333): (family with sequence similarity 114 member A2)

FAM114A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM114A2	NM_018691.4 link	c.940A>G	p.Thr314Ala	missense_variant	Exon 9 of 14	ENST00000351797.9	NP_061161.2	Q9NRY5A0A140VKG4I6L9D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FAM114A2	ENST00000351797.9 link	c.940A>G	p.Thr314Ala	missense_variant	Exon 9 of 14	1	NM_018691.4	ENSP00000341597.4	Q9NRY5
FAM114A2	ENST00000520667.5 link	c.940A>G	p.Thr314Ala	missense_variant	Exon 10 of 15	1		ENSP00000430384.1	Q9NRY5
FAM114A2	ENST00000522858.5 link	c.940A>G	p.Thr314Ala	missense_variant	Exon 9 of 14	1		ENSP00000430489.1	Q9NRY5
FAM114A2	ENST00000520313.5 link	c.730A>G	p.Thr244Ala	missense_variant	Exon 8 of 13	2		ENSP00000429088.1	E7ESJ7

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000401

AC:

AN:

249606

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

134858

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0000294

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000708

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000979

AC:

143

AN:

1460576

Hom.:

Cov.:

AF XY:

0.0000991

AC XY:

AN XY:

726570

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000124

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0000722

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000197

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.940A>G (p.T314A) alteration is located in exon 9 (coding exon 8) of the FAM114A2 gene. This alteration results from a A to G substitution at nucleotide position 940, causing the threonine (T) at amino acid position 314 to be replaced by an alanine (A). 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

Benign

0.084

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;T;T;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.77

.;.;T;T

M_CAP

Benign

0.011

MetaRNN

Uncertain

0.53

D;D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.0

M;M;M;.

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-4.1

D;D;D;D

REVEL

Benign

0.15

Sift

Uncertain

0.0050

D;D;D;D

Sift4G

Uncertain

0.022

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.69

MVP

0.21

MPC

0.070

ClinPred

0.64

GERP RS

4.7

Varity_R

0.21

gMVP

0.19

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

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