Genetic Variant FAM78B:p.Glu227Lys (chr1-166070348-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001017961.5(FAM78B):c.679G>A(p.Glu227Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,016 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FAM78B
NM_001017961.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.00

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 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
FAM78B	NM_001017961.5 link	c.679G>A	p.Glu227Lys	missense_variant	Exon 2 of 2	ENST00000354422.4	NP_001017961.1	Q5VT40F1T0K0
FAM78B	NM_001320302.2 link	c.264-9685G>A		intron_variant	Intron 1 of 1		NP_001307231.1	F1T0K0
FAM78B	NR_135199.2 link	n.1432G>A		non_coding_transcript_exon_variant	Exon 2 of 3
FAM78B	NR_163271.1 link	n.1186G>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.679G>A	p.Glu227Lys	missense_variant	Exon 2 of 2	2	NM_001017961.5	ENSP00000346404.3		Q5VT40

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249728

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134878

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:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460016

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726120

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.679G>A (p.E227K) 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 679, causing the glutamic acid (E) at amino acid position 227 to be replaced by a lysine (K). 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

0.93

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.062

T;T

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.80

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.69

D;D

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.9

N;N

REVEL

Pathogenic

0.78

Sift

Benign

0.36

T;T

Sift4G

Uncertain

0.029

D;D

Polyphen

1.0

D;D

Vest4

0.60

MutPred

0.56

Gain of MoRF binding (P = 0.0065);Gain of MoRF binding (P = 0.0065);

MVP

0.92

MPC

1.2

ClinPred

0.88

GERP RS

5.7

Varity_R

0.32

gMVP

0.56

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