Genetic Variant FAM228A:p.Lys54Arg (chr2-24177869-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001040710.3(FAM228A):c.161A>G(p.Lys54Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000394 in 1,600,730 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/26 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 2 hom. )

Consequence

FAM228A
NM_001040710.3 missense, splice_region

Scores

Splicing: ADA: 0.2648

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.75

Publications

4 publications found

Variant links:

Genes affected

FAM228A (HGNC:34418): (family with sequence similarity 228 member A)

FAM228A links:

ENSG00000276087 (HGNC:):

ENSG00000276087 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17646089).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040710.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM228A	NM_001040710.3	MANE Select	c.161A>G	p.Lys54Arg	missense splice_region	Exon 3 of 6	NP_001035800.1	Q86W67

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM228A	ENST00000295150.8	TSL:1 MANE Select	c.161A>G	p.Lys54Arg	missense splice_region	Exon 3 of 6	ENSP00000295150.3	Q86W67
ENSG00000276087	ENST00000610442.1	TSL:2	n.*1288A>G		splice_region non_coding_transcript_exon	Exon 11 of 14	ENSP00000483650.1	A0A087X0T9
ENSG00000276087	ENST00000610442.1	TSL:2	n.*1288A>G		3_prime_UTR	Exon 11 of 14	ENSP00000483650.1	A0A087X0T9

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000823

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000281

AC:

AN:

245762

AF XY:

0.000270

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000399

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000468

Gnomad NFE exome

AF:

0.000533

Gnomad OTH exome

AF:

0.000504

GnomAD4 exome

AF:

0.000394

AC:

570

AN:

1448500

Hom.:

Cov.:

AF XY:

0.000413

AC XY:

298

AN XY:

721196

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33158

American (AMR)

AF:

0.00

AC:

AN:

44112

Ashkenazi Jewish (ASJ)

AF:

0.000307

AC:

AN:

26018

East Asian (EAS)

AF:

0.00

AC:

AN:

39446

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84992

European-Finnish (FIN)

AF:

0.000132

AC:

AN:

53172

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.000488

AC:

538

AN:

1101884

Other (OTH)

AF:

0.000250

AC:

AN:

59974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

109

136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000394

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000823

AC:

AN:

68044

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000544

Hom.:

Bravo

AF:

0.000314

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000484

AC:

ExAC

AF:

0.000372

AC:

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

0.14

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Benign

0.18

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.43

M_CAP

Benign

0.013

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.1

PhyloP100

2.7

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.3

REVEL

Benign

0.25

Sift

Benign

0.083

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.38

MVP

0.27

MPC

0.29

ClinPred

0.12

GERP RS

3.1

Varity_R

0.096

gMVP

0.062

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.26

dbscSNV1_RF

Benign

0.44

SpliceAI score (max)

0.37

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.37

Position offset: 1

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over