rs771168491

Variant names:

• chrX-134852893-T-C
• rs771168491
• NM_001388447.1:c.683T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001388447.1(PABIR3):​c.683T>C​(p.Val228Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,102,461 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V228V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000089 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.00011 (0 hom. 27 hem.)
• Consequence: PABIR3 NM_001388447.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.855
• Publications: 2 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04155293).
• BP6: Variant X-134852893-T-C is Benign according to our data. Variant chrX-134852893-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2661482.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• 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.683T>C	p.Val228Ala	missense_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.683T>C	p.Val228Ala	missense_variant	Exon 10 of 11		NM_001388447.1	ENSP00000496338.1

Frequencies

GnomAD3 genomes AF: 0.0000895 AC: 10 AN: 111781 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: 0.000555

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000150

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000192 AC: 15 AN: 78222 AF XY: 0.000309

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000710

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000322

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000111 AC: 110 AN: 990629 Hom.: 0 Cov.: 21 AF XY: 0.0000905 AC XY: 27 AN XY: 298351

African (AFR) AF: 0.00 AC: 0 AN: 23298

American (AMR) AF: 0.00 AC: 0 AN: 22084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17546

East Asian (EAS) AF: 0.000232 AC: 6 AN: 25883

South Asian (SAS) AF: 0.00 AC: 0 AN: 43176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26241

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3922

European-Non Finnish (NFE) AF: 0.000131 AC: 103 AN: 786114

Other (OTH) AF: 0.0000236 AC: 1 AN: 42365

GnomAD4 genome AF: 0.0000894 AC: 10 AN: 111832 Hom.: 0 Cov.: 23 AF XY: 0.0000882 AC XY: 3 AN XY: 34016

African (AFR) AF: 0.00 AC: 0 AN: 30848

American (AMR) AF: 0.00 AC: 0 AN: 10447

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

East Asian (EAS) AF: 0.000556 AC: 2 AN: 3594

South Asian (SAS) AF: 0.00 AC: 0 AN: 2713

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5929

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000150 AC: 8 AN: 53233

Other (OTH) AF: 0.00 AC: 0 AN: 1523

Alfa AF: 0.0000869 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.000210 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.439T>C (p.C147R) alteration is located in exon 6 (coding exon 6) of the FAM122C gene. This alteration results from a T to C substitution at nucleotide position 439, causing the cysteine (C) at amino acid position 147 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PABIR3: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.029
DANN	Benign	0.17
DEOGEN2	Benign	0.011	T
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.85
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.026
Sift	Uncertain	0.029	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0060	B
Vest4		0.21
MVP		0.66
MPC		0.85
ClinPred		0.037	T
GERP RS		1.1
Varity_R		0.41
gMVP		0.15
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs771168491; hg19: chrX-133986923;