12-8222114-G-T

Variant names:

• chr12-8222114-G-T
• rs150580216
• NM_018088.3:c.1103C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018088.3(FAM90A1):​c.1103C>A​(p.Pro368His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P368R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FAM90A1 NM_018088.3 missense
• Clinical Significance: Not reported in ClinVar
• 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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.111199945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM90A1	NM_018088.3	c.1103C>A	p.Pro368His	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.1103C>A	p.Pro368His	missense_variant	Exon 7 of 7	1	NM_018088.3	ENSP00000445418.1
FAM90A1	ENST00000307435.10	c.1103C>A	p.Pro368His	missense_variant	Exon 6 of 6	2		ENSP00000307798.6
FAM66C	ENST00000736407.1	n.588-3772G>T		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459288 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726028

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4404

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111996

Other (OTH) AF: 0.0000166 AC: 1 AN: 60240

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0066	N
LIST_S2	Benign	0.43	.;T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		1.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Benign	0.030
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.43	B;B
Vest4		0.19
MutPred		0.25		Loss of glycosylation at P368 (P = 0.0244);Loss of glycosylation at P368 (P = 0.0244);
MVP		0.17
MPC		1.0
ClinPred		0.58	D
GERP RS		-1.4
Varity_R		0.33
gMVP		0.061
Mutation Taster		=100/0	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

Publications

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Other links and lift over

dbSNP: rs150580216; hg19: chr12-8374710;