12-109768214-C-G

Variant names:

• chr12-109768214-C-G
• rs1889115876
• NM_032829.3:c.285C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM2 PM5 PP2 BP4_Moderate

The NM_032829.3(FAM222A):​c.285C>G​(p.His95Gln) 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. 15/22 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. H95Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FAM222A NM_032829.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.398
• Publications: 0 publications found

Genes affected

FAM222A (HGNC:25915): (family with sequence similarity 222 member A)

FAM222A-AS1 (HGNC:28223): (FAM222A antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-109768213-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 402150.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.1231 (below the threshold of 3.09). Trascript score misZ: -0.076601 (below the threshold of 3.09).
• BP4: Computational evidence support a benign effect (MetaRNN=0.17536932).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032829.3. 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
	FAM222A	NM_032829.3	MANE Select	c.285C>G	p.His95Gln	missense	Exon 3 of 3	NP_116218.2	Q5U5X8
	FAM222A-AS1	NR_026661.2		n.191+5083G>C		intron	N/A
	FAM222A-AS1	NR_026662.2		n.191+5083G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM222A	ENST00000538780.2	TSL:1 MANE Select	c.285C>G	p.His95Gln	missense	Exon 3 of 3	ENSP00000443292.1	Q5U5X8
	FAM222A	ENST00000358906.3	TSL:5	c.285C>G	p.His95Gln	missense	Exon 3 of 3	ENSP00000351783.3	Q5U5X8
	FAM222A	ENST00000898959.1		c.285C>G	p.His95Gln	missense	Exon 2 of 2	ENSP00000569018.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	3.3
DANN	Benign	0.80
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L
PhyloP100		-0.40
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.19
Sift	Benign	0.44	T
Sift4G	Benign	0.52	T
Polyphen		0.12	B
Vest4		0.69
MutPred		0.23		Gain of disorder (P = 0.0627)
MVP		0.014
MPC		0.68
ClinPred		0.40	T
GERP RS		-0.70
Varity_R		0.081
gMVP		0.43
Mutation Taster		=71/29	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: rs1889115876; hg19: chr12-110206019;