Genetic Variant FAM118B:p.Lys237Thr (chr11-126256580-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024556.4(FAM118B):c.710A>C(p.Lys237Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

FAM118B
NM_024556.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.74

Variant links:

Genes affected

FAM118B (HGNC:26110): (family with sequence similarity 118 member B) Enables identical protein binding activity. Predicted to be involved in Cajal body organization. Predicted to be located in Cajal body. [provided by Alliance of Genome Resources, Apr 2022]

FAM118B links:

SRPRA (HGNC:11307): (SRP receptor subunit alpha) The gene encodes a subunit of the endoplasmic reticulum signal recognition particle receptor that, in conjunction with the signal recognition particle, is involved in the targeting and translocation of signal sequence tagged secretory and membrane proteins across the endoplasmic reticulum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

SRPRA links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17720085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM118B	NM_024556.4 link	c.710A>C	p.Lys237Thr	missense_variant	Exon 7 of 9	ENST00000533050.6	NP_078832.1	Q9BPY3A0A024R3L8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM118B	ENST00000533050.6 link	c.710A>C	p.Lys237Thr	missense_variant	Exon 7 of 9	1	NM_024556.4	ENSP00000433343.1		Q9BPY3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251052

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461280

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726990

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000180

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.710A>C (p.K237T) alteration is located in exon 7 (coding exon 5) of the FAM118B gene. This alteration results from a A to C substitution at nucleotide position 710, causing the lysine (K) at amino acid position 237 to be replaced by a threonine (T). 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

0.19

BayesDel_addAF

Benign

-0.059

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.028

T;T;T;T;T;T

Eigen

Benign

0.079

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

D;D;D;.;D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.18

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

N;.;.;.;.;.

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.59

N;.;N;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.074

T;.;T;T;D;T

Sift4G

Benign

0.064

T;T;T;T;T;T

Polyphen

0.95

P;P;P;P;.;.

Vest4

0.45

MutPred

0.26

Loss of ubiquitination at K237 (P = 0.027);.;Loss of ubiquitination at K237 (P = 0.027);.;Loss of ubiquitination at K237 (P = 0.027);.;

MVP

0.53

MPC

0.26

ClinPred

0.25

GERP RS

5.0

Varity_R

0.17

gMVP

0.69

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