chr22-45328059-C-T

Position:

• chr22-45328059-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017911.4(FAM118A):​c.518C>T​(p.Thr173Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 27)
• Consequence: FAM118A NM_017911.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74

Genes affected

FAM118A (HGNC:1313): (family with sequence similarity 118 member A) Enables identical protein binding activity. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

FAM118A (HGNC:):

ACMG classification

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=0.12365818).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM118A	NM_017911.4	c.518C>T	p.Thr173Ile	missense_variant	4/9	ENST00000441876.7	NP_060381.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM118A	ENST00000441876.7	c.518C>T	p.Thr173Ile	missense_variant	4/9	1	NM_017911.4	ENSP00000395892.2
FAM118A	ENST00000216214.7	c.518C>T	p.Thr173Ile	missense_variant	5/10	2		ENSP00000216214.3
FAM118A	ENST00000405673.5	c.518C>T	p.Thr173Ile	missense_variant	4/5	5		ENSP00000385231.1
FAM118A	ENST00000477714.1	n.574C>T		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 16

GnomAD4 genome Cov.: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 04, 2024

The c.518C>T (p.T173I) alteration is located in exon 5 (coding exon 3) of the FAM118A gene. This alteration results from a C to T substitution at nucleotide position 518, causing the threonine (T) at amino acid position 173 to be replaced by an isoleucine (I). 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	0.21
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T;T;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.86	.;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	N;N;D
REVEL	Benign	0.043
Sift	Benign	0.20	T;T;D
Sift4G	Uncertain	0.054	T;T;D
Polyphen		0.21	B;B;.
Vest4		0.33
MutPred		0.27		Loss of disorder (P = 0.0339);Loss of disorder (P = 0.0339);Loss of disorder (P = 0.0339);
MVP		0.17
MPC		0.25
ClinPred		0.49	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.072
gMVP		0.38

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

Other links and lift over

dbSNP: rs1257955606; hg19: chr22-45723940;