chr12-8221952-G-A

Variant names:

• chr12-8221952-G-A
• rs552829155
• NM_018088.3:c.1265C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018088.3(FAM90A1):​c.1265C>T​(p.Ala422Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,596,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A422G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: FAM90A1 NM_018088.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.114
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052847266).

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.1265C>T	p.Ala422Val	missense	Exon 7 of 7	NP_060558.3	Q86YD7
	FAM90A1	NM_001319982.2		c.1265C>T	p.Ala422Val	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.1265C>T	p.Ala422Val	missense	Exon 7 of 7	ENSP00000445418.1	Q86YD7
	FAM90A1	ENST00000307435.10	TSL:2	c.1265C>T	p.Ala422Val	missense	Exon 6 of 6	ENSP00000307798.6	Q86YD7
	FAM90A1	ENST00000890758.1		c.1265C>T	p.Ala422Val	missense	Exon 7 of 7	ENSP00000560817.1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152222 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000184 AC: 43 AN: 233864 AF XY: 0.000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00336

Gnomad EAS exome AF: 0.0000555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000460

Gnomad OTH exome AF: 0.000506

GnomAD4 exome AF: 0.000154 AC: 222 AN: 1444152 Hom.: 0 Cov.: 31 AF XY: 0.000147 AC XY: 106 AN XY: 718826

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

African (AFR) AF: 0.0000599 AC: 2 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00573 AC: 149 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1111648

Other (OTH) AF: 0.000366 AC: 22 AN: 60094

⚠️ 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 AF: 0.000269 AC: 41 AN: 152222 Hom.: 0 Cov.: 34 AF XY: 0.000269 AC XY: 20 AN XY: 74364

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

African (AFR) AF: 0.0000724 AC: 3 AN: 41460

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000990 Hom.: 0

ExAC AF: 0.000280 AC: 33

EpiCase AF: 0.000109

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	0.098
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.3
DANN	Benign	0.95
DEOGEN2	Benign	0.0033	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0045	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.11
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.039
Sift	Benign	0.16	T
Sift4G	Benign	0.093	T
Polyphen		0.0060	B
Vest4		0.12
MutPred		0.10		Loss of phosphorylation at S427 (P = 0.2407)
MVP		0.11
MPC		0.30
ClinPred		0.014	T
GERP RS		1.1
Varity_R		0.042
gMVP		0.025
Mutation Taster		=99/1	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: rs552829155; hg19: chr12-8374548;