Genetic Variant FAM221B:p.Val292Ile (chr9-35819374-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001012446.4(FAM221B):c.874G>A(p.Val292Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,551,648 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict 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. V292L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0094 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 17 hom. )

Consequence

FAM221B
NM_001012446.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0190

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025111735).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00943 (1436/152300) while in subpopulation AFR AF= 0.033 (1370/41552). AF 95% confidence interval is 0.0315. There are 12 homozygotes in gnomad4. There are 699 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM221B	NM_001012446.4 link	c.874G>A	p.Val292Ile	missense_variant	Exon 5 of 7	ENST00000423537.7	NP_001012448.2	A6H8Z2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM221B	ENST00000423537.7 link	c.874G>A	p.Val292Ile	missense_variant	Exon 5 of 7	1	NM_001012446.4	ENSP00000415299.2		A6H8Z2-1
ENSG00000285645	ENST00000650284.1 link	n.64+1G>A		splice_donor_variant, intron_variant	Intron 4 of 9			ENSP00000498023.1		A0A3B3IU11

Frequencies

GnomAD3 genomes

AF:

0.00944

AC:

1437

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0331

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

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:

0.0000588

Gnomad OTH

AF:

0.00862

GnomAD3 exomes

AF:

0.00208

AC:

325

AN:

156278

Hom.:

AF XY:

0.00165

AC XY:

137

AN XY:

82834

show subpopulations

Gnomad AFR exome

AF:

0.0348

Gnomad AMR exome

AF:

0.00166

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000439

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000497

Gnomad OTH exome

AF:

0.000911

GnomAD4 exome

AF:

0.00106

AC:

1485

AN:

1399348

Hom.:

Cov.:

AF XY:

0.000894

AC XY:

617

AN XY:

690192

show subpopulations

Gnomad4 AFR exome

AF:

0.0370

Gnomad4 AMR exome

AF:

0.00162

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000631

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000834

Gnomad4 OTH exome

AF:

0.00259

GnomAD4 genome

AF:

0.00943

AC:

1436

AN:

152300

Hom.:

Cov.:

AF XY:

0.00939

AC XY:

699

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0330

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00853

Alfa

AF:

0.000605

Hom.:

Bravo

AF:

0.0111

ESP6500AA

AF:

0.0354

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00293

AC:

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0053

T;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.61

T;T

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.40

N;N

REVEL

Benign

0.016

Sift

Benign

0.070

T;T

Sift4G

Benign

0.26

T;.

Polyphen

0.51

P;.

Vest4

0.15

MVP

0.030

MPC

0.10

ClinPred

0.0063

GERP RS

1.8

Varity_R

0.030

gMVP

0.21

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over