Genetic Variant FAM221B:p.Arg306Leu (chr9-35819331-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001012446.4(FAM221B):c.917G>T(p.Arg306Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000572 in 1,399,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R306H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

FAM221B
NM_001012446.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.31

Publications

0 publications found

Variant links:

Genes affected

FAM221B (HGNC:30762): (family with sequence similarity 221 member B)

FAM221B links:

ENSG00000285645 (HGNC:):

ENSG00000285645 links:

TMEM8B (HGNC:21427): (transmembrane protein 8B) Involved in cell-matrix adhesion. Located in cell surface and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM8B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32801926).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012446.4. 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
	FAM221B	NM_001012446.4	MANE Select	c.917G>T	p.Arg306Leu	missense	Exon 5 of 7	NP_001012448.2	A6H8Z2-1
	FAM221B	NR_052026.2		n.1378G>T		non_coding_transcript_exon	Exon 6 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM221B	ENST00000423537.7	TSL:1 MANE Select	c.917G>T	p.Arg306Leu	missense	Exon 5 of 7	ENSP00000415299.2	A6H8Z2-1
FAM221B	ENST00000388950.8	TSL:1	n.*85G>T		non_coding_transcript_exon	Exon 6 of 8	ENSP00000373602.4	A6H8Z2-3
FAM221B	ENST00000388950.8	TSL:1	n.*85G>T		3_prime_UTR	Exon 6 of 8	ENSP00000373602.4	A6H8Z2-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000572

AC:

AN:

1399410

Hom.:

Cov.:

AF XY:

0.00000435

AC XY:

AN XY:

690220

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31598

American (AMR)

AF:

0.00

AC:

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.00

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00000741

AC:

AN:

1078970

Other (OTH)

AF:

0.00

AC:

AN:

58004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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

Uncertain

0.53

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.040

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.81

M_CAP

Benign

0.025

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.6

PhyloP100

3.3

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-5.5

REVEL

Benign

0.23

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0

Polyphen

0.97

Vest4

0.50

MutPred

0.40

Loss of loop (P = 0.0374)

MVP

0.28

MPC

0.39

ClinPred

0.99

GERP RS

5.1

Varity_R

0.39

gMVP

0.59

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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