X-134829262-C-T

Variant names:

• chrX-134829262-C-T
• rs143835393
• NM_001388447.1:c.226C>T

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.226C>T​(p.Arg76Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,205,538 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 91 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. R76H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.00027 (0 hom. 88 hem.)
• Consequence: PABIR3 NM_001388447.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23
• 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=0.15515485).
• BS2: High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABIR3	NM_001388447.1	c.226C>T	p.Arg76Cys	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.226C>T	p.Arg76Cys	missense_variant	Exon 4 of 11		NM_001388447.1	ENSP00000496338.1

Frequencies

GnomAD3 genomes AF: 0.000189 AC: 21 AN: 111060 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000327

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: 0.000377

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000824 AC: 15 AN: 182115 AF XY: 0.0000300

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000369

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000172

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000269 AC: 294 AN: 1094478 Hom.: 0 Cov.: 28 AF XY: 0.000244 AC XY: 88 AN XY: 360102

African (AFR) AF: 0.0000380 AC: 1 AN: 26342

American (AMR) AF: 0.0000570 AC: 2 AN: 35100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19311

East Asian (EAS) AF: 0.00 AC: 0 AN: 30130

South Asian (SAS) AF: 0.00 AC: 0 AN: 53580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40458

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

European-Non Finnish (NFE) AF: 0.000336 AC: 282 AN: 839482

Other (OTH) AF: 0.000196 AC: 9 AN: 45948

GnomAD4 genome AF: 0.000189 AC: 21 AN: 111060 Hom.: 0 Cov.: 23 AF XY: 0.0000901 AC XY: 3 AN XY: 33314

African (AFR) AF: 0.0000327 AC: 1 AN: 30584

American (AMR) AF: 0.00 AC: 0 AN: 10353

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3574

South Asian (SAS) AF: 0.00 AC: 0 AN: 2664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.000377 AC: 20 AN: 53009

Other (OTH) AF: 0.00 AC: 0 AN: 1497

Alfa AF: 0.000218 Hom.: 7

Bravo AF: 0.000332

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.226C>T (p.R76C) alteration is located in exon 3 (coding exon 3) of the FAM122C gene. This alteration results from a C to T substitution at nucleotide position 226, causing the arginine (R) at amino acid position 76 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	0.14
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;.;T;.;.
FATHMM_MKL	Benign	0.063	N
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	2.0	.;.;M;M;.
PhyloP100		1.2
PrimateAI	Benign	0.20	T
PROVEAN	Pathogenic	-4.4	.;.;D;D;.
REVEL	Benign	0.17
Sift	Uncertain	0.0010	.;.;D;D;.
Sift4G	Pathogenic	0.0010	.;.;D;D;.
Polyphen		0.24, 0.21	.;.;B;B;.
Vest4		0.27, 0.30
MVP		0.95
MPC		0.75
ClinPred		0.24	T
GERP RS		2.5
Varity_R		0.39
gMVP		0.49
Mutation Taster		=96/4	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: rs143835393; hg19: chrX-133963292;