Genetic Variant FAM221B:p.Thr379Ile (chr9-35818925-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001012446.4(FAM221B):c.1136C>T(p.Thr379Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00002 in 1,399,634 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

FAM221B
NM_001012446.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.01

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM221B	NM_001012446.4 link	c.1136C>T	p.Thr379Ile	missense_variant	Exon 6 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.1136C>T	p.Thr379Ile	missense_variant	Exon 6 of 7	1	NM_001012446.4	ENSP00000415299.2		A6H8Z2-1
ENSG00000285645	ENST00000650284.1 link	n.149C>T		non_coding_transcript_exon_variant	Exon 5 of 10			ENSP00000498023.1		A0A3B3IU11

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000635

AC:

AN:

157480

Hom.:

AF XY:

0.0000120

AC XY:

AN XY:

83332

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000163

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000200

AC:

AN:

1399634

Hom.:

Cov.:

AF XY:

0.0000217

AC XY:

AN XY:

690328

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000259

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000368

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1136C>T (p.T379I) alteration is located in exon 6 (coding exon 5) of the FAM221B gene. This alteration results from a C to T substitution at nucleotide position 1136, causing the threonine (T) at amino acid position 379 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.093

Eigen

Uncertain

0.35

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.58

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.52

MetaSVM

Benign

-0.98

MutationAssessor

Pathogenic

3.1

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-4.1

REVEL

Benign

0.096

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.63

MutPred

0.27

Loss of disorder (P = 0.0206);

MVP

0.29

MPC

0.39

ClinPred

0.96

GERP RS

3.5

Varity_R

0.25

gMVP

0.52

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over