Genetic Variant FAM78B:p.Arg221Gln (chr1-166070365-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

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

The NM_001017961.5(FAM78B):c.662G>A(p.Arg221Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,613,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

FAM78B
NM_001017961.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.48

Variant links:

Genes affected

FAM78B (HGNC:13495): (family with sequence similarity 78 member B)

FAM78B 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=0.034370035).

BS2

High AC in GnomAd4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM78B	NM_001017961.5 link	c.662G>A	p.Arg221Gln	missense_variant	Exon 2 of 2	ENST00000354422.4	NP_001017961.1	Q5VT40F1T0K0
FAM78B	NM_001320302.2 link	c.264-9702G>A		intron_variant	Intron 1 of 1		NP_001307231.1	F1T0K0
FAM78B	NR_135199.2 link	n.1415G>A		non_coding_transcript_exon_variant	Exon 2 of 3
FAM78B	NR_163271.1 link	n.1169G>A		non_coding_transcript_exon_variant	Exon 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM78B	ENST00000354422.4 link	c.662G>A	p.Arg221Gln	missense_variant	Exon 2 of 2	2	NM_001017961.5	ENSP00000346404.3		Q5VT40

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000718

AC:

AN:

250582

Hom.:

AF XY:

0.0000813

AC XY:

AN XY:

135370

show subpopulations

Gnomad AFR exome

AF:

0.000800

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:

0.0000353

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461268

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

726862

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000217

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000906

Hom.:

Bravo

AF:

0.000272

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.662G>A (p.R221Q) alteration is located in exon 2 (coding exon 2) of the FAM78B gene. This alteration results from a G to A substitution at nucleotide position 662, causing the arginine (R) at amino acid position 221 to be replaced by a glutamine (Q). 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

Benign

0.14

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.014

T;T

Eigen

Benign

-0.13

Eigen_PC

Benign

0.067

FATHMM_MKL

Benign

0.43

LIST_S2

Uncertain

0.90

.;D

M_CAP

Benign

0.0023

MetaRNN

Benign

0.034

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.19

N;N

PrimateAI

Uncertain

0.60

PROVEAN

Benign

0.49

N;N

REVEL

Benign

0.12

Sift

Benign

0.61

T;T

Sift4G

Benign

0.98

T;T

Polyphen

0.63

P;P

Vest4

0.11

MVP

0.068

MPC

0.92

ClinPred

0.041

GERP RS

4.6

Varity_R

0.12

gMVP

0.30

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