12-8222074-G-T

Variant names:

• chr12-8222074-G-T
• rs1948836191
• NM_018088.3:c.1143C>A

Variant summary

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

The NM_018088.3(FAM90A1):​c.1143C>A​(p.His381Gln) 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. 13/20 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: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FAM90A1 NM_018088.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09790039).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM90A1	NM_018088.3	c.1143C>A	p.His381Gln	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.1143C>A	p.His381Gln	missense_variant	Exon 7 of 7	1	NM_018088.3	ENSP00000445418.1
FAM90A1	ENST00000307435.10	c.1143C>A	p.His381Gln	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: 6.87e-7 AC: 1 AN: 1455756 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724376

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1143C>A (p.H381Q) alteration is located in exon 7 (coding exon 4) of the FAM90A1 gene. This alteration results from a C to A substitution at nucleotide position 1143, causing the histidine (H) at amino acid position 381 to be replaced by a glutamine (Q). 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	0.20
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.2
DANN	Benign	0.89
DEOGEN2	Benign	0.0017	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0032	N
LIST_S2	Benign	0.36	.;T
M_CAP	Benign	0.00083	T
MetaRNN	Benign	0.098	T;T
MetaSVM	Benign	-0.98	T
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.041
Sift	Benign	0.40	T;T
Sift4G	Benign	0.55	T;T
Polyphen		0.55	P;P
Vest4		0.21
MutPred		0.27		Loss of catalytic residue at H381 (P = 0.1384);Loss of catalytic residue at H381 (P = 0.1384);
MVP		0.085
MPC		0.50
ClinPred		0.17	T
GERP RS		-2.0
Varity_R		0.065
gMVP		0.040

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: rs1948836191; hg19: chr12-8374670;