rs1311098250

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• 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
• Publications: 0 publications found

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]

FAM66C (HGNC:21644): (family with sequence similarity 66 member C)

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=0.27678782).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018088.3. 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
	FAM90A1	NM_018088.3	MANE Select	c.1127G>A	p.Cys376Tyr	missense	Exon 7 of 7	NP_060558.3	Q86YD7
	FAM90A1	NM_001319982.2		c.1127G>A	p.Cys376Tyr	missense	Exon 6 of 6	NP_001306911.1	Q86YD7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM90A1	ENST00000538603.6	TSL:1 MANE Select	c.1127G>A	p.Cys376Tyr	missense	Exon 7 of 7	ENSP00000445418.1	Q86YD7
	FAM90A1	ENST00000307435.10	TSL:2	c.1127G>A	p.Cys376Tyr	missense	Exon 6 of 6	ENSP00000307798.6	Q86YD7
	FAM90A1	ENST00000890758.1		c.1127G>A	p.Cys376Tyr	missense	Exon 7 of 7	ENSP00000560817.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000817 AC: 2 AN: 244816 AF XY: 0.0000150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86172

European-Finnish (FIN) AF: 0.0000197 AC: 1 AN: 50756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4316

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111964

Other (OTH) AF: 0.0000332 AC: 2 AN: 60222

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	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
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
MetaSVM	Benign	-1.0	T
PhyloP100		-0.071
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.048
Sift	Benign	0.11	T
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.28
MutPred		0.41		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
Mutation Taster		=97/3	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: rs1311098250; hg19: chr12-8374686;