Genetic Variant NM_001376049.1:c.1077G>T (chr5-74800906-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001376049.1(FAM169A):c.1077G>T(p.Gln359His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FAM169A
NM_001376049.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.306

Publications

0 publications found

Variant links:

Genes affected

FAM169A (HGNC:29138): (family with sequence similarity 169 member A) Predicted to be located in nuclear inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

FAM169A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376049.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM169A	NM_001376049.1	MANE Select	c.1077G>T	p.Gln359His	missense	Exon 10 of 13	NP_001362978.1	Q9Y6X4-1
FAM169A	NM_001376050.1		c.1077G>T	p.Gln359His	missense	Exon 10 of 13	NP_001362979.1	Q9Y6X4-1
FAM169A	NM_001376051.1		c.1077G>T	p.Gln359His	missense	Exon 10 of 13	NP_001362980.1	Q9Y6X4-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM169A	ENST00000687041.1	MANE Select	c.1077G>T	p.Gln359His	missense	Exon 10 of 13	ENSP00000508577.1	Q9Y6X4-1
FAM169A	ENST00000389156.9	TSL:1	c.1077G>T	p.Gln359His	missense	Exon 10 of 13	ENSP00000373808.4	Q9Y6X4-1
FAM169A	ENST00000510609.5	TSL:1	n.*521G>T		non_coding_transcript_exon	Exon 9 of 12	ENSP00000423905.1	Q9Y6X4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.45e-7

AC:

AN:

1342140

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

664966

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29160

American (AMR)

AF:

0.00

AC:

AN:

33438

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23320

East Asian (EAS)

AF:

0.00

AC:

AN:

33244

South Asian (SAS)

AF:

0.0000155

AC:

AN:

64460

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48920

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5412

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1049652

Other (OTH)

AF:

0.00

AC:

AN:

54534

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.011

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.62

M_CAP

Benign

0.012

MetaRNN

Benign

0.085

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

0.31

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.30

REVEL

Benign

0.040

Sift

Benign

0.16

Sift4G

Benign

0.32

Polyphen

0.0030

Vest4

0.13

MutPred

0.12

Loss of methylation at K356 (P = 0.1008)

MVP

0.043

MPC

0.22

ClinPred

0.13

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.040

gMVP

0.15

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.27

Position offset: 23

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over