rs374009398

Variant names:

• chrX-134781845-G-A
• rs374009398
• NM_001387468.1:c.635C>T

Variant summary

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

The NM_001387468.1(PABIR2):​c.635C>T​(p.Ala212Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000953 in 1,196,219 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 32 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 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. A212T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000093 (0 hom. 30 hem.)
• Consequence: PABIR2 NM_001387468.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.25
• Publications: 7 publications found

Genes affected

PABIR2 (HGNC:30490): (PABIR family member 2) Predicted to enable protein serine/threonine phosphatase inhibitor activity. Predicted to be involved in negative regulation of catalytic activity. Predicted to be part of collagen trimer. [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=0.11880526).
• BS2: High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABIR2	NM_001387468.1	c.635C>T	p.Ala212Val	missense_variant	Exon 9 of 10	ENST00000343004.10	NP_001374397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PABIR2	ENST00000343004.10	c.635C>T	p.Ala212Val	missense_variant	Exon 9 of 10	1	NM_001387468.1	ENSP00000339207.6

Frequencies

GnomAD3 genomes AF: 0.000117 AC: 13 AN: 110911 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000764

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000755

Gnomad OTH AF: 0.00134

GnomAD2 exomes AF: 0.000141 AC: 25 AN: 177686 AF XY: 0.000112

Gnomad AFR exome AF: 0.000232

Gnomad AMR exome AF: 0.000152

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000249

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.0000931 AC: 101 AN: 1085256 Hom.: 0 Cov.: 27 AF XY: 0.0000849 AC XY: 30 AN XY: 353424

African (AFR) AF: 0.0000381 AC: 1 AN: 26217

American (AMR) AF: 0.000115 AC: 4 AN: 34736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19093

East Asian (EAS) AF: 0.0000333 AC: 1 AN: 30022

South Asian (SAS) AF: 0.000577 AC: 30 AN: 51999

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39508

Middle Eastern (MID) AF: 0.000491 AC: 2 AN: 4075

European-Non Finnish (NFE) AF: 0.0000611 AC: 51 AN: 834060

Other (OTH) AF: 0.000263 AC: 12 AN: 45546

GnomAD4 genome AF: 0.000117 AC: 13 AN: 110963 Hom.: 0 Cov.: 23 AF XY: 0.0000602 AC XY: 2 AN XY: 33249

African (AFR) AF: 0.000163 AC: 5 AN: 30589

American (AMR) AF: 0.00 AC: 0 AN: 10334

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

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

South Asian (SAS) AF: 0.000766 AC: 2 AN: 2611

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5840

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

European-Non Finnish (NFE) AF: 0.0000755 AC: 4 AN: 52961

Other (OTH) AF: 0.00133 AC: 2 AN: 1506

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000157 AC: 19

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.632C>T (p.A211V) alteration is located in exon 9 (coding exon 9) of the FAM122B gene. This alteration results from a C to T substitution at nucleotide position 632, causing the alanine (A) at amino acid position 211 to be replaced by a valine (V). 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	0.087
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;.;.;.;T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;T;T;T;T;.
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.12	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.4	M;.;.;.;.;.
PhyloP100		6.3
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.73	N;.;N;N;.;.
REVEL	Benign	0.21
Sift	Benign	0.079	T;.;D;T;.;.
Sift4G	Uncertain	0.037	D;D;T;D;D;D
Polyphen		0.88	P;.;.;P;P;.
Vest4		0.18
MVP		0.76
MPC		0.75
ClinPred		0.039	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.092
gMVP		0.26
Mutation Taster		=98/2	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: rs374009398; hg19: chrX-133915875; COSMIC: COSV53231540;