Variant 9-35819912-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000423537.7(FAM221B):c.831G>T(p.Leu277Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,613,856 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 10 hom. )

Consequence

FAM221B
ENST00000423537.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.413

Variant links:

Genes affected

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

FAM221B 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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049294233).

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM221B	NM_001012446.4 linkuse as main transcript	c.831G>T	p.Leu277Phe	missense_variant	4/7	ENST00000423537.7	NP_001012448.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM221B	ENST00000423537.7 linkuse as main transcript	c.831G>T	p.Leu277Phe	missense_variant	4/7	1	NM_001012446.4	ENSP00000415299	P1	A6H8Z2-1
FAM221B	ENST00000377984.2 linkuse as main transcript	c.831G>T	p.Leu277Phe	missense_variant	5/6	1		ENSP00000367222
FAM221B	ENST00000388950.8 linkuse as main transcript	c.1022G>T	p.Ter341LeuextTer15	stop_lost, NMD_transcript_variant	5/8	1		ENSP00000373602		A6H8Z2-3
TMEM8B	ENST00000377996.5 linkuse as main transcript	c.-451+3678C>A		intron_variant		2		ENSP00000367235		A6NDV4-2

Frequencies

GnomAD3 genomes

AF:

0.00140

AC:

213

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00200

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00143

AC:

356

AN:

249536

Hom.:

AF XY:

0.00134

AC XY:

182

AN XY:

135390

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00334

Gnomad NFE exome

AF:

0.00196

Gnomad OTH exome

AF:

0.00297

GnomAD4 exome

AF:

0.00230

AC:

3364

AN:

1461584

Hom.:

Cov.:

AF XY:

0.00223

AC XY:

1619

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.000827

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00404

Gnomad4 NFE exome

AF:

0.00271

Gnomad4 OTH exome

AF:

0.00126

GnomAD4 genome

AF:

0.00140

AC:

213

AN:

152272

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

110

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00229

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00226

Gnomad4 NFE

AF:

0.00200

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00168

Hom.:

Bravo

AF:

0.00121

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00241

AC:

ExAC

AF:

0.00142

AC:

171

EpiCase

AF:

0.000981

EpiControl

AF:

0.00184

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2021

The c.831G>T (p.L277F) alteration is located in exon 4 (coding exon 3) of the FAM221B gene. This alteration results from a G to T substitution at nucleotide position 831, causing the leucine (L) at amino acid position 277 to be replaced by a phenylalanine (F). 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

Pathogenic

0.63

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.011

T;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.61

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;.

MutationTaster

Benign

1.0

N;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.058

Sift

Benign

0.23

T;T

Sift4G

Benign

0.11

T;.

Polyphen

0.41

B;.

Vest4

0.35

MutPred

0.35

Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);

MVP

0.048

MPC

0.26

ClinPred

0.025

GERP RS

-0.19

Varity_R

0.074

gMVP

0.49

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