Genetic Variant NM_001394345.1:c.337A>G (chr1-222749560-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001394345.1(FAM177B):c.337A>G(p.Lys113Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000064 in 1,562,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict 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 (★). Synonymous variant affecting the same amino acid position (i.e. K113K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

FAM177B
NM_001394345.1 missense, splice_region

Scores

Splicing: ADA: 0.001843

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.671

Publications

0 publications found

Variant links:

Genes affected

FAM177B (HGNC:34395): (family with sequence similarity 177 member B)

FAM177B links:

ENSG00000287684 (HGNC:):

ENSG00000287684 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10739976).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394345.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM177B	NM_001394345.1	MANE Select	c.337A>G	p.Lys113Glu	missense splice_region	Exon 5 of 6	NP_001381274.1	A6PVY3-1
FAM177B	NM_001324080.2		c.337A>G	p.Lys113Glu	missense splice_region	Exon 4 of 5	NP_001311009.1	A6PVY3-1
FAM177B	NM_207468.3		c.337A>G	p.Lys113Glu	missense splice_region	Exon 5 of 6	NP_997351.2	A6PVY3-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM177B	ENST00000445590.4	TSL:5 MANE Select	c.337A>G	p.Lys113Glu	missense splice_region	Exon 5 of 6	ENSP00000414451.2	A6PVY3-1
FAM177B	ENST00000360827.6	TSL:5	c.337A>G	p.Lys113Glu	missense splice_region	Exon 5 of 6	ENSP00000354070.2	A6PVY3-1
FAM177B	ENST00000893418.1		c.337A>G	p.Lys113Glu	missense splice_region	Exon 4 of 5	ENSP00000563477.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152216

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000414

AC:

AN:

241598

AF XY:

0.00000763

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000900

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000496

AC:

AN:

1410214

Hom.:

Cov.:

AF XY:

0.00000426

AC XY:

AN XY:

704050

show subpopulations

African (AFR)

AF:

0.0000933

AC:

AN:

32164

American (AMR)

AF:

0.00

AC:

AN:

43184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25618

East Asian (EAS)

AF:

0.00

AC:

AN:

39380

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53052

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.00000281

AC:

AN:

1069154

Other (OTH)

AF:

0.00

AC:

AN:

58608

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.00000378

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

0.079

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0044

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.45

M_CAP

Benign

0.0074

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.67

PhyloP100

0.67

PrimateAI

Benign

0.33

PROVEAN

Benign

0.57

REVEL

Benign

0.12

Sift

Benign

0.86

Sift4G

Benign

0.93

Polyphen

0.95

Vest4

0.19

MutPred

0.24

Loss of MoRF binding (P = 0.003)

MVP

0.030

MPC

0.29

ClinPred

0.18

GERP RS

4.0

Varity_R

0.15

gMVP

0.066

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0018

dbscSNV1_RF

Benign

0.050

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over