Genetic Variant FAM222B:p.Arg396His (chr17-28758772-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001077498.3(FAM222B):c.1187G>A(p.Arg396His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000382 in 1,572,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R396C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

FAM222B
NM_001077498.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.37

Publications

0 publications found

Variant links:

Genes affected

FAM222B (HGNC:25563): (family with sequence similarity 222 member B) Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

FAM222B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.067968726).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077498.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM222B	NM_001077498.3	MANE Select	c.1187G>A	p.Arg396His	missense	Exon 3 of 3	NP_001070966.1	Q8WU58
FAM222B	NM_001288631.2		c.1193G>A	p.Arg398His	missense	Exon 4 of 4	NP_001275560.1
FAM222B	NM_001288632.2		c.1187G>A	p.Arg396His	missense	Exon 5 of 5	NP_001275561.1	Q8WU58

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM222B	ENST00000581407.6	TSL:1 MANE Select	c.1187G>A	p.Arg396His	missense	Exon 3 of 3	ENSP00000462419.1	Q8WU58
FAM222B	ENST00000582266.6	TSL:1	c.*988G>A		3_prime_UTR	Exon 3 of 3	ENSP00000462534.1	J3KSK8
FAM222B	ENST00000452648.8	TSL:2	c.1187G>A	p.Arg396His	missense	Exon 3 of 3	ENSP00000413645.3	Q8WU58

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152236

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:

0.000193

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:

0.0000210

AC:

AN:

190090

AF XY:

0.0000292

show subpopulations

Gnomad AFR exome

AF:

0.0000957

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000223

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000352

AC:

AN:

1419876

Hom.:

Cov.:

AF XY:

0.00000570

AC XY:

AN XY:

701522

show subpopulations

African (AFR)

AF:

0.0000308

AC:

AN:

32490

American (AMR)

AF:

0.00

AC:

AN:

38682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25430

East Asian (EAS)

AF:

0.0000535

AC:

AN:

37378

South Asian (SAS)

AF:

0.00

AC:

AN:

82026

European-Finnish (FIN)

AF:

0.0000199

AC:

AN:

50126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

9.18e-7

AC:

AN:

1089318

Other (OTH)

AF:

0.00

AC:

AN:

58706

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

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:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000333

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

0.19

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

Eigen

Benign

0.064

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.018

MetaRNN

Benign

0.068

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

3.4

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.38

REVEL

Benign

0.088

Sift

Uncertain

0.025

Sift4G

Uncertain

0.024

Polyphen

0.93

Vest4

0.29

MutPred

0.35

Loss of methylation at R396 (P = 0.0197)

MVP

0.043

MPC

0.53

ClinPred

0.60

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.092

gMVP

0.53

Mutation Taster

=90/10

polymorphism

(source)

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

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over