11-126261461-C-A

Variant names:

• chr11-126261461-C-A
• rs756594266
• NM_024556.4:c.1019C>A

Variant summary

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

The NM_024556.4(FAM118B):​c.1019C>A​(p.Ser340Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,514 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

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]

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]

ACMG classification

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
FAM118B	NM_024556.4	c.1019C>A	p.Ser340Tyr	missense_variant	Exon 8 of 9	ENST00000533050.6	NP_078832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM118B	ENST00000533050.6	c.1019C>A	p.Ser340Tyr	missense_variant	Exon 8 of 9	1	NM_024556.4	ENSP00000433343.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251430 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461514 Hom.: 0 Cov.: 29 AF XY: 0.00000825 AC XY: 6 AN XY: 727094

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1019C>A (p.S340Y) alteration is located in exon 8 (coding exon 6) of the FAM118B gene. This alteration results from a C to A substitution at nucleotide position 1019, causing the serine (S) at amino acid position 340 to be replaced by a tyrosine (Y). 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	0.099
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	T;T;T;T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.92	D;D;D;.;D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.072	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N;.;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.6	N;.;N;N;N
REVEL	Benign	0.068
Sift	Uncertain	0.0030	D;.;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;D
Polyphen		0.025	B;P;B;P;.
Vest4		0.54
MutPred		0.20		Loss of disorder (P = 0.0073);.;.;.;.;
MVP		0.38
MPC		0.27
ClinPred		0.14	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: 23

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs756594266; hg19: chr11-126131356;