chr22-45323251-G-A

Variant names:

• chr22-45323251-G-A
• rs2085010222
• NM_017911.4:c.124G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017911.4(FAM118A):​c.124G>A​(p.Val42Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FAM118A NM_017911.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.75
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4004071).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017911.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM118A	NM_017911.4	MANE Select	c.124G>A	p.Val42Met	missense	Exon 3 of 9	NP_060381.2	Q9NWS6-1
	FAM118A	NM_001349916.2		c.166G>A	p.Val56Met	missense	Exon 5 of 11	NP_001336845.1
	FAM118A	NM_001349914.2		c.127G>A	p.Val43Met	missense	Exon 3 of 9	NP_001336843.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM118A	ENST00000441876.7	TSL:1 MANE Select	c.124G>A	p.Val42Met	missense	Exon 3 of 9	ENSP00000395892.2	Q9NWS6-1
	FAM118A	ENST00000894424.1		c.127G>A	p.Val43Met	missense	Exon 4 of 10	ENSP00000564483.1
	FAM118A	ENST00000894426.1		c.127G>A	p.Val43Met	missense	Exon 3 of 9	ENSP00000564485.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.20
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.66
MutPred		0.27		Gain of glycosylation at P44 (P = 0.1426)
MVP		0.34
MPC		0.59
ClinPred		0.94	D
GERP RS		5.6
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.7
Varity_R		0.23
gMVP		0.66
Mutation Taster		=57/43	polymorphism

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

Other links and lift over

dbSNP: rs2085010222; hg19: chr22-45719132; COSMIC: COSV53419821; COSMIC: COSV53419821;