X-134845384-G-A

Variant names:

• chrX-134845384-G-A
• rs369818916
• NM_001388447.1:c.328G>A

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.328G>A​(p.Glu110Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000074 in 1,203,096 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.000075 (0 hom. 22 hem.)
• Consequence: PABIR3 NM_001388447.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66
• 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=0.21400762).
• 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.328G>A	p.Glu110Lys	missense_variant	Exon 6 of 11	ENST00000645433.2	NP_001375376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PABIR3	ENST00000645433.2	c.328G>A	p.Glu110Lys	missense_variant	Exon 6 of 11		NM_001388447.1	ENSP00000496338.1

Frequencies

GnomAD3 genomes AF: 0.0000624 AC: 7 AN: 112104 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000131

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000172 AC: 3 AN: 174160 AF XY: 0.0000166

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: 0.0000377

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000752 AC: 82 AN: 1090992 Hom.: 0 Cov.: 29 AF XY: 0.0000615 AC XY: 22 AN XY: 357726

African (AFR) AF: 0.0000383 AC: 1 AN: 26083

American (AMR) AF: 0.00 AC: 0 AN: 33621

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19235

East Asian (EAS) AF: 0.00 AC: 0 AN: 30032

South Asian (SAS) AF: 0.00 AC: 0 AN: 52269

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3808

European-Non Finnish (NFE) AF: 0.0000917 AC: 77 AN: 839616

Other (OTH) AF: 0.0000873 AC: 4 AN: 45842

GnomAD4 genome AF: 0.0000624 AC: 7 AN: 112104 Hom.: 0 Cov.: 23 AF XY: 0.0000875 AC XY: 3 AN XY: 34274

African (AFR) AF: 0.00 AC: 0 AN: 30911

American (AMR) AF: 0.00 AC: 0 AN: 10479

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3605

South Asian (SAS) AF: 0.00 AC: 0 AN: 2741

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6031

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.000131 AC: 7 AN: 53257

Other (OTH) AF: 0.00 AC: 0 AN: 1508

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000567

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000549

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.328G>A (p.E110K) alteration is located in exon 5 (coding exon 5) of the FAM122C gene. This alteration results from a G to A substitution at nucleotide position 328, causing the glutamic acid (E) at amino acid position 110 to be replaced by a lysine (K). 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	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;.;T;.;.
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.88	D;D;D;T;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.21	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	.;.;L;L;.
PhyloP100		1.7
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.8	.;.;D;D;.
REVEL	Benign	0.065
Sift	Uncertain	0.0030	.;.;D;D;.
Sift4G	Uncertain	0.010	.;.;D;T;.
Polyphen		0.15	.;.;B;B;.
Vest4		0.16, 0.17
MVP		0.81
MPC		0.25
ClinPred		0.30	T
GERP RS		1.6
Varity_R		0.35
gMVP		0.45
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs369818916; hg19: chrX-133979414;