X-134814841-C-T

Variant names:

• chrX-134814841-C-T
• rs201102053
• NM_001388447.1:c.181C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001388447.1(PABIR3):​c.181C>T​(p.Arg61Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000286 in 1,190,066 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000029 (0 hom. 8 hem.)
• Consequence: PABIR3 NM_001388447.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.582
• Publications: 3 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056217045).
• BS2: High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABIR3	NM_001388447.1	c.181C>T	p.Arg61Cys	missense_variant	Exon 3 of 11	ENST00000645433.2	NP_001375376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PABIR3	ENST00000645433.2	c.181C>T	p.Arg61Cys	missense_variant	Exon 3 of 11		NM_001388447.1	ENSP00000496338.1

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 112017 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000952

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: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000412 AC: 7 AN: 169913 AF XY: 0.0000357

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000407

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000516

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000288 AC: 31 AN: 1077997 Hom.: 0 Cov.: 26 AF XY: 0.0000231 AC XY: 8 AN XY: 345599

African (AFR) AF: 0.00 AC: 0 AN: 25728

American (AMR) AF: 0.00 AC: 0 AN: 33602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18969

East Asian (EAS) AF: 0.0000336 AC: 1 AN: 29727

South Asian (SAS) AF: 0.0000775 AC: 4 AN: 51615

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40222

Middle Eastern (MID) AF: 0.000246 AC: 1 AN: 4060

European-Non Finnish (NFE) AF: 0.0000278 AC: 23 AN: 828753

Other (OTH) AF: 0.0000441 AC: 2 AN: 45321

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 112069 Hom.: 0 Cov.: 23 AF XY: 0.0000584 AC XY: 2 AN XY: 34255

African (AFR) AF: 0.00 AC: 0 AN: 30904

American (AMR) AF: 0.0000951 AC: 1 AN: 10515

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3596

South Asian (SAS) AF: 0.00 AC: 0 AN: 2743

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5993

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53241

Other (OTH) AF: 0.00 AC: 0 AN: 1522

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.181C>T (p.R61C) alteration is located in exon 2 (coding exon 2) of the FAM122C gene. This alteration results from a C to T substitution at nucleotide position 181, causing the arginine (R) at amino acid position 61 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	0.098
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.027	.;.;.;.;T;.;.
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.37	T;T;T;T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.056	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	.;.;.;.;N;N;.
PhyloP100		0.58
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-2.2	N;.;.;.;N;N;.
REVEL	Benign	0.13
Sift	Uncertain	0.0070	D;.;.;.;D;D;.
Sift4G	Uncertain	0.0040	D;.;.;T;D;D;.
Polyphen		0.62	.;.;.;.;P;P;.
Vest4		0.041
MVP		0.59
MPC		0.22
ClinPred		0.20	T
GERP RS		4.5
Varity_R		0.11
gMVP		0.32
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs201102053; hg19: chrX-133948871; COSMIC: COSV66194337; COSMIC: COSV66194337;