rs757576648

Variant names:

• chr12-109768398-T-G
• rs757576648
• NM_032829.3:c.469T>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2 BP4_Strong

The NM_032829.3(FAM222A):​c.469T>G​(p.Leu157Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00002 in 1,598,248 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: FAM222A NM_032829.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.86
• 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: Likely_benign. The variant received -3 ACMG points.

• 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=0.040070027).

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.469T>G	p.Leu157Val	missense	Exon 3 of 3	NP_116218.2	Q5U5X8
	FAM222A-AS1	NR_026661.2		n.191+4899A>C		intron	N/A
	FAM222A-AS1	NR_026662.2		n.191+4899A>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.469T>G	p.Leu157Val	missense	Exon 3 of 3	ENSP00000443292.1	Q5U5X8
	FAM222A	ENST00000358906.3	TSL:5	c.469T>G	p.Leu157Val	missense	Exon 3 of 3	ENSP00000351783.3	Q5U5X8
	FAM222A	ENST00000898959.1		c.469T>G	p.Leu157Val	missense	Exon 2 of 2	ENSP00000569018.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152082 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000225 AC: 5 AN: 221816 AF XY: 0.0000162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000593

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000201

Gnomad OTH exome AF: 0.000180

GnomAD4 exome AF: 0.0000173 AC: 25 AN: 1446166 Hom.: 0 Cov.: 31 AF XY: 0.0000181 AC XY: 13 AN XY: 719552

African (AFR) AF: 0.0000899 AC: 3 AN: 33386

American (AMR) AF: 0.0000450 AC: 2 AN: 44398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.00 AC: 0 AN: 85822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41208

Middle Eastern (MID) AF: 0.000869 AC: 5 AN: 5754

European-Non Finnish (NFE) AF: 0.00000901 AC: 10 AN: 1110046

Other (OTH) AF: 0.0000833 AC: 5 AN: 60034

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152082 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74300

African (AFR) AF: 0.0000483 AC: 2 AN: 41414

American (AMR) AF: 0.000196 AC: 3 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000334 AC: 4

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	0.067
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.84
DANN	Benign	0.94
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.7	L
PhyloP100		-1.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.053
Sift	Benign	0.10	T
Sift4G	Benign	0.31	T
Polyphen		0.10	B
Vest4		0.075
MutPred		0.080		Loss of glycosylation at P156 (P = 0.1668)
MVP		0.030
MPC		0.24
ClinPred		0.15	T
GERP RS		-4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.056
gMVP		0.11
Mutation Taster		=95/5	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: rs757576648; hg19: chr12-110206203;