chr12-109768167-A-G

Position:

• chr12-109768167-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032829.3(FAM222A):​c.238A>G​(p.Asn80Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FAM222A NM_032829.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.59

Genes affected

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

FAM222A-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM222A	NM_032829.3	c.238A>G	p.Asn80Asp	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.238A>G	p.Asn80Asp	missense_variant	3/3	1	NM_032829.3	ENSP00000443292.1
FAM222A	ENST00000358906.3	c.238A>G	p.Asn80Asp	missense_variant	3/3	5		ENSP00000351783.3
FAM222A-AS1	ENST00000541460.2	n.189+5130T>C		intron_variant		4
FAM222A-AS1	ENST00000541723.5	n.212+5130T>C		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461494 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Jul 02, 2024

The c.238A>G (p.N80D) alteration is located in exon 3 (coding exon 2) of the FAM222A gene. This alteration results from a A to G substitution at nucleotide position 238, causing the asparagine (N) at amino acid position 80 to be replaced by an aspartic acid (D). 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	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.28	T
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.044	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.44		Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);
MVP		0.44
MPC		0.73
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.84
gMVP		0.61

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

LitVar

Other links and lift over

dbSNP: rs954599216; hg19: chr12-110205972;