X-134829254-C-G

Variant names:

• chrX-134829254-C-G
• rs752986755
• NM_001388447.1:c.218C>G

Variant summary

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

The NM_001388447.1(PABIR3):​c.218C>G​(p.Ser73Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000829 in 1,206,324 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000082 (0 hom. 4 hem.)
• Consequence: PABIR3 NM_001388447.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.371
• 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=0.11715746).
• BS2: High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABIR3	NM_001388447.1	c.218C>G	p.Ser73Cys	missense_variant	Exon 4 of 11	ENST00000645433.2	NP_001375376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PABIR3	ENST00000645433.2	c.218C>G	p.Ser73Cys	missense_variant	Exon 4 of 11		NM_001388447.1	ENSP00000496338.1

Frequencies

GnomAD3 genomes AF: 0.00000898 AC: 1 AN: 111331 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000965

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000493 AC: 9 AN: 182436 AF XY: 0.0000747

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000221

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 9 AN: 1094993 Hom.: 0 Cov.: 28 AF XY: 0.0000111 AC XY: 4 AN XY: 360565

African (AFR) AF: 0.00 AC: 0 AN: 26348

American (AMR) AF: 0.000142 AC: 5 AN: 35123

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19324

East Asian (EAS) AF: 0.00 AC: 0 AN: 30144

South Asian (SAS) AF: 0.0000558 AC: 3 AN: 53737

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 839739

Other (OTH) AF: 0.00 AC: 0 AN: 45977

GnomAD4 genome AF: 0.00000898 AC: 1 AN: 111331 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33513

African (AFR) AF: 0.00 AC: 0 AN: 30656

American (AMR) AF: 0.0000965 AC: 1 AN: 10366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3583

South Asian (SAS) AF: 0.00 AC: 0 AN: 2675

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53097

Other (OTH) AF: 0.00 AC: 0 AN: 1499

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.218C>G (p.S73C) alteration is located in exon 3 (coding exon 3) of the FAM122C gene. This alteration results from a C to G substitution at nucleotide position 218, causing the serine (S) at amino acid position 73 to be replaced by a cysteine (C). 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	0.10
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.020	.;.;T;.;.
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.33	T;T;T;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	.;.;L;L;.
PhyloP100		0.37
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.97	.;.;N;N;.
REVEL	Benign	0.087
Sift	Benign	0.047	.;.;D;T;.
Sift4G	Uncertain	0.052	.;.;T;T;.
Polyphen		0.18	.;.;B;B;.
Vest4		0.15, 0.18
MutPred		0.30		Loss of disorder (P = 0.0064);Loss of disorder (P = 0.0064);Loss of disorder (P = 0.0064);Loss of disorder (P = 0.0064);Loss of disorder (P = 0.0064);
MVP		0.66
MPC		0.62
ClinPred		0.082	T
GERP RS		3.3
Varity_R		0.11
gMVP		0.21
Mutation Taster		=84/16	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: rs752986755; hg19: chrX-133963284;