Genetic Variant FAM86B1:p.Arg251Leu (chr8-12185414-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001083537.4(FAM86B1):c.752G>T(p.Arg251Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R251H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FAM86B1
NM_001083537.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.06

Publications

1 publications found

Variant links:

Genes affected

FAM86B1 (HGNC:28268): (family with sequence similarity 86 member B1) Predicted to enable methyltransferase activity. Predicted to be involved in methylation. [provided by Alliance of Genome Resources, Apr 2022]

FAM86B1 links:

FAM66D (HGNC:24159): (family with sequence similarity 66 member D)

FAM66D links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.851

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083537.4. 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
	FAM86B1	NM_001083537.4	MANE Select	c.752G>T	p.Arg251Leu	missense	Exon 6 of 7	NP_001077006.1	Q8N7N1-2
	FAM86B1	NR_003494.3		n.549G>T		non_coding_transcript_exon	Exon 5 of 6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM86B1	ENST00000448228.7	TSL:5 MANE Select	c.752G>T	p.Arg251Leu	missense	Exon 6 of 7	ENSP00000407067.2	Q8N7N1-2
FAM86B1	ENST00000524893.5	TSL:1	n.*302G>T		non_coding_transcript_exon	Exon 4 of 5	ENSP00000436024.1	E9PLW5
FAM86B1	ENST00000524893.5	TSL:1	n.*302G>T		3_prime_UTR	Exon 4 of 5	ENSP00000436024.1	E9PLW5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000895

AC:

AN:

223436

AF XY:

0.0000164

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:

0.0000506

Gnomad NFE exome

AF:

0.00000966

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000486

AC:

AN:

1440066

Hom.:

Cov.:

AF XY:

0.00000419

AC XY:

AN XY:

716168

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:

33240

American (AMR)

AF:

0.00

AC:

AN:

43424

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25860

East Asian (EAS)

AF:

0.00

AC:

AN:

38180

South Asian (SAS)

AF:

0.00

AC:

AN:

83494

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52210

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5198

European-Non Finnish (NFE)

AF:

0.00000637

AC:

AN:

1098962

Other (OTH)

AF:

0.00

AC:

AN:

59498

⚠️ 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: 0.282

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.23

Eigen_PC

Benign

-0.053

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.022

MetaRNN

Pathogenic

0.85

MetaSVM

Benign

-0.50

MutationAssessor

Pathogenic

4.5

PhyloP100

5.1

PROVEAN

Pathogenic

-5.4

REVEL

Benign

0.21

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0050

Polyphen

0.95

Vest4

0.81

MutPred

0.69

Loss of catalytic residue at R285 (P = 0.0152)

MVP

0.26

MPC

3.7

ClinPred

0.99

GERP RS

1.2

Varity_R

0.64

gMVP

0.77

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over