chrX-134807618-A-T

Variant names:

• chrX-134807618-A-T
• rs781575411
• NM_001388447.1:c.20A>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.20A>T​(p.Lys7Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000488 in 1,208,892 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 23 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000052 (0 hom. 21 hem.)
• Consequence: PABIR3 NM_001388447.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.23
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026669621).
• 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.20A>T	p.Lys7Ile	missense_variant	Exon 2 of 11	ENST00000645433.2	NP_001375376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PABIR3	ENST00000645433.2	c.20A>T	p.Lys7Ile	missense_variant	Exon 2 of 11		NM_001388447.1	ENSP00000496338.1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111730 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: 0.00

Gnomad SAS AF: 0.000746

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000203 AC: 37 AN: 181959 AF XY: 0.000226

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000520 AC: 57 AN: 1097162 Hom.: 0 Cov.: 30 AF XY: 0.0000579 AC XY: 21 AN XY: 362568

African (AFR) AF: 0.00 AC: 0 AN: 26383

American (AMR) AF: 0.00 AC: 0 AN: 35142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19347

East Asian (EAS) AF: 0.00 AC: 0 AN: 30153

South Asian (SAS) AF: 0.00100 AC: 54 AN: 53962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40511

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841494

Other (OTH) AF: 0.0000652 AC: 3 AN: 46036

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111730 Hom.: 0 Cov.: 23 AF XY: 0.0000590 AC XY: 2 AN XY: 33904

African (AFR) AF: 0.00 AC: 0 AN: 30753

American (AMR) AF: 0.00 AC: 0 AN: 10503

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2633

East Asian (EAS) AF: 0.00 AC: 0 AN: 3570

South Asian (SAS) AF: 0.000746 AC: 2 AN: 2681

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6047

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53109

Other (OTH) AF: 0.00 AC: 0 AN: 1509

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.000288 AC: 35

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.20A>T (p.K7I) alteration is located in exon 1 (coding exon 1) of the FAM122C gene. This alteration results from a A to T substitution at nucleotide position 20, causing the lysine (K) at amino acid position 7 to be replaced by an isoleucine (I). 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	0.15
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.094	.;.;.;.;.;.;T;.;T;T;.;.
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.88	.;D;D;D;D;D;D;D;.;D;D;D
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.027	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;.;.;.;.;.;N;N;.;.;.;.
PhyloP100		2.2
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-4.4	.;.;D;.;.;.;D;D;.;.;.;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	.;.;D;.;.;.;D;D;.;.;.;.
Sift4G	Uncertain	0.0020	.;.;D;.;.;D;D;D;.;.;.;.
Polyphen		0.17	.;.;.;.;.;.;B;B;.;.;.;.
Vest4		0.14, 0.26, 0.22, 0.26
MutPred		0.41		.;.;.;Loss of disorder (P = 0.0011);Loss of disorder (P = 0.0011);Loss of disorder (P = 0.0011);Loss of disorder (P = 0.0011);Loss of disorder (P = 0.0011);Loss of disorder (P = 0.0011);Loss of disorder (P = 0.0011);Loss of disorder (P = 0.0011);Loss of disorder (P = 0.0011);
MVP		0.80
MPC		0.31
ClinPred		0.16	T
GERP RS		4.4
PromoterAI		-0.70	Under-expression
Varity_R		0.34
gMVP		0.34
Mutation Taster		=91/9	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: rs781575411; hg19: chrX-133941648;