12-109768214-C-G

Position:

• chr12-109768214-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 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. 14/21 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. H95L) has been classified as Pathogenic.

• 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

Genes affected

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

FAM222A-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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 Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.17536932).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM222A	NM_032829.3	c.285C>G	p.His95Gln	missense_variant	3/3	ENST00000538780.2	NP_116218.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM222A	ENST00000538780.2	c.285C>G	p.His95Gln	missense_variant	3/3	1	NM_032829.3	ENSP00000443292.1
FAM222A	ENST00000358906.3	c.285C>G	p.His95Gln	missense_variant	3/3	5		ENSP00000351783.3
FAM222A-AS1	ENST00000541460.2	n.189+5083G>C		intron_variant		4
FAM222A-AS1	ENST00000541723.5	n.212+5083G>C		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2023

The c.285C>G (p.H95Q) alteration is located in exon 3 (coding exon 2) of the FAM222A gene. This alteration results from a C to G substitution at nucleotide position 285, causing the histidine (H) at amino acid position 95 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	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	3.3
DANN	Benign	0.80
DEOGEN2	Benign	0.016	T;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;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L;L
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.19
Sift	Benign	0.44	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.12	B;B
Vest4		0.69
MutPred		0.23		Gain of disorder (P = 0.0627);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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-110206019;