rs754469983

Variant names:

• chrX-134854118-C-T
• rs754469983
• ENST00000370784.8:c.470C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP7 BS2

The NM_001388447.1(PABIR3):​c.714C>T​(p.Asn238Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,209,271 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000015 (0 hom. 7 hem.)
• Consequence: PABIR3 NM_001388447.1 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.111
• Publications: 3 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09842965).
• BP7: Synonymous conserved (PhyloP=0.111 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABIR3	NM_001388447.1	c.714C>T	p.Asn238Asn	synonymous_variant	Exon 11 of 11	ENST00000645433.2	NP_001375376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PABIR3	ENST00000645433.2	c.714C>T	p.Asn238Asn	synonymous_variant	Exon 11 of 11		NM_001388447.1	ENSP00000496338.1

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111914 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: 0.000279

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000549 AC: 10 AN: 182165 AF XY: 0.0000900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000652

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 16 AN: 1097357 Hom.: 0 Cov.: 29 AF XY: 0.0000193 AC XY: 7 AN XY: 362739

African (AFR) AF: 0.00 AC: 0 AN: 26388

American (AMR) AF: 0.00 AC: 0 AN: 35146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19373

East Asian (EAS) AF: 0.000431 AC: 13 AN: 30174

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 53949

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40479

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841645

Other (OTH) AF: 0.0000217 AC: 1 AN: 46068

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111914 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34080

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30798

American (AMR) AF: 0.00 AC: 0 AN: 10463

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.000279 AC: 1 AN: 3589

South Asian (SAS) AF: 0.00 AC: 0 AN: 2722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6006

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53240

Other (OTH) AF: 0.00 AC: 0 AN: 1522

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 15, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.470C>T (p.T157M) alteration is located in exon 7 (coding exon 7) of the FAM122C gene. This alteration results from a C to T substitution at nucleotide position 470, causing the threonine (T) at amino acid position 157 to be replaced by a methionine (M). 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	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	1.4
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.11
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.23
MutPred		0.36		Loss of catalytic residue at T157 (P = 0.183);
MVP		0.79
MPC		0.66
ClinPred		0.21	T
GERP RS		3.4
Varity_R		0.091
gMVP		0.25
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs754469983; hg19: chrX-133988148; COSMIC: COSV66196250; COSMIC: COSV66196250;