ENST00000370784.8:c.440G>A

Variant names:

• chrX-134852894-G-A
• rs1352254279
• ENST00000370784.8:c.440G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000370784.8(PABIR3):​c.440G>A​(p.Cys147Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,100,184 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. C147R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 3 hem.)
• Consequence: PABIR3 ENST00000370784.8 missense, splice_region
• Scores: Splicing: ADA: 0.00003792
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0910
• Publications: 0 publications found

Genes affected

PABIR3 (HGNC:25202): (PABIR family member 3) Predicted to enable protein serine/threonine phosphatase inhibitor activity. Predicted to be involved in negative regulation of catalytic activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10648039).
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABIR3	NM_001388447.1	c.684G>A	p.Val228Val	splice_region_variant, synonymous_variant	Exon 10 of 11	ENST00000645433.2	NP_001375376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PABIR3	ENST00000645433.2	c.684G>A	p.Val228Val	splice_region_variant, synonymous_variant	Exon 10 of 11		NM_001388447.1	ENSP00000496338.1

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111716 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000101 AC: 10 AN: 988468 Hom.: 0 Cov.: 21 AF XY: 0.0000101 AC XY: 3 AN XY: 296684

African (AFR) AF: 0.00 AC: 0 AN: 23245

American (AMR) AF: 0.00 AC: 0 AN: 22060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17524

East Asian (EAS) AF: 0.00 AC: 0 AN: 25818

South Asian (SAS) AF: 0.00 AC: 0 AN: 43018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3912

European-Non Finnish (NFE) AF: 0.0000127 AC: 10 AN: 784377

Other (OTH) AF: 0.00 AC: 0 AN: 42288

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111716 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33900

African (AFR) AF: 0.00 AC: 0 AN: 30757

American (AMR) AF: 0.00 AC: 0 AN: 10425

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3599

South Asian (SAS) AF: 0.00 AC: 0 AN: 2717

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53231

Other (OTH) AF: 0.00 AC: 0 AN: 1503

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.440G>A (p.C147Y) alteration is located in exon 6 (coding exon 6) of the FAM122C gene. This alteration results from a G to A substitution at nucleotide position 440, causing the cysteine (C) at amino acid position 147 to be replaced by a tyrosine (Y). 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	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.15
DANN	Benign	0.95
DEOGEN2	Benign	0.019	T
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.091
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.057
Sift	Uncertain	0.022	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.32
MutPred		0.28		Loss of methylation at K144 (P = 0.0556);
MVP		0.80
MPC		0.83
ClinPred		0.16	T
GERP RS		1.1
Varity_R		0.18
gMVP		0.19
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.14		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: rs1352254279; hg19: chrX-133986924;