12-8222090-C-T

Variant names:

• chr12-8222090-C-T
• rs1311098250
• NM_018088.3:c.1127G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018088.3(FAM90A1):​c.1127G>A​(p.Cys376Tyr) 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. 12/20 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: 34)
  • Exomes 𝑓: 0.000016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FAM90A1 NM_018088.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0710

Genes affected

FAM90A1 (HGNC:25526): (family with sequence similarity 90 member A1) FAM90A1 belongs to subfamily I of the primate-specific FAM90A gene family, which originated from multiple duplications and rearrangements (Bosch et al., 2007 [PubMed 17684299]).[supplied by OMIM, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27678782).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM90A1	NM_018088.3	c.1127G>A	p.Cys376Tyr	missense_variant	Exon 7 of 7	ENST00000538603.6	NP_060558.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM90A1	ENST00000538603.6	c.1127G>A	p.Cys376Tyr	missense_variant	Exon 7 of 7	1	NM_018088.3	ENSP00000445418.1
FAM90A1	ENST00000307435.10	c.1127G>A	p.Cys376Tyr	missense_variant	Exon 6 of 6	2		ENSP00000307798.6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000158 AC: 23 AN: 1457404 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 725130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000197

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 34

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1127G>A (p.C376Y) alteration is located in exon 7 (coding exon 4) of the FAM90A1 gene. This alteration results from a G to A substitution at nucleotide position 1127, causing the cysteine (C) at amino acid position 376 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	0.24
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.027	T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.0081	N
LIST_S2	Benign	0.54	.;T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Benign	0.048
Sift	Benign	0.11	T;T
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;D
Vest4		0.28
MutPred		0.41		Gain of phosphorylation at C376 (P = 0.0235);Gain of phosphorylation at C376 (P = 0.0235);
MVP		0.27
MPC		1.3
ClinPred		0.54	D
GERP RS		-0.034
Varity_R		0.15
gMVP		0.062

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: rs1311098250; hg19: chr12-8374686;