rs758401189

Variant names:

• chrX-151621001-T-G
• rs758401189
• NM_173493.3:c.279T>G

Variant summary

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

The NM_173493.3(PASD1):​c.279T>G​(p.Ile93Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,199,199 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000018 (0 hom. 8 hem.)
• Consequence: PASD1 NM_173493.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.12
• Publications: 0 publications found

Genes affected

PASD1 (HGNC:20686): (PAS domain containing repressor 1) This gene encodes a protein that is thought to function as a transcription factor. The protein is a cancer-associated antigen that can stimulate autologous T-cell responses, and it is therefore considered to be a potential immunotherapeutic target for the treatment of various hematopoietic malignancies, including diffuse large B-cell lymphoma. [provided by RefSeq, May 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.072410375).
• BS2: High Hemizygotes in GnomAdExome4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PASD1	NM_173493.3	c.279T>G	p.Ile93Met	missense_variant	Exon 5 of 16	ENST00000370357.5	NP_775764.2
PASD1	XM_011531102.3	c.279T>G	p.Ile93Met	missense_variant	Exon 5 of 16		XP_011529404.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PASD1	ENST00000370357.5	c.279T>G	p.Ile93Met	missense_variant	Exon 5 of 16	1	NM_173493.3	ENSP00000359382.4
PASD1	ENST00000464219.1	n.417T>G		non_coding_transcript_exon_variant	Exon 5 of 15	2

Frequencies

GnomAD3 genomes AF: 0.00000896 AC: 1 AN: 111650 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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 7 AN: 175908 AF XY: 0.0000819

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: 0.0000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000184 AC: 20 AN: 1087549 Hom.: 0 Cov.: 27 AF XY: 0.0000226 AC XY: 8 AN XY: 353893

African (AFR) AF: 0.00 AC: 0 AN: 26084

American (AMR) AF: 0.00 AC: 0 AN: 34662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19180

East Asian (EAS) AF: 0.00 AC: 0 AN: 29937

South Asian (SAS) AF: 0.00 AC: 0 AN: 52493

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40370

Middle Eastern (MID) AF: 0.000244 AC: 1 AN: 4094

European-Non Finnish (NFE) AF: 0.0000216 AC: 18 AN: 835068

Other (OTH) AF: 0.0000219 AC: 1 AN: 45661

GnomAD4 genome AF: 0.00000896 AC: 1 AN: 111650 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33846

African (AFR) AF: 0.00 AC: 0 AN: 30737

American (AMR) AF: 0.00 AC: 0 AN: 10477

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3580

South Asian (SAS) AF: 0.00 AC: 0 AN: 2660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6056

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

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53066

Other (OTH) AF: 0.00 AC: 0 AN: 1506

Alfa AF: 0.0000868 Hom.: 1

Bravo AF: 0.00000378

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.279T>G (p.I93M) alteration is located in exon 5 (coding exon 4) of the PASD1 gene. This alteration results from a T to G substitution at nucleotide position 279, causing the isoleucine (I) at amino acid position 93 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	-0.59
CADD	Benign	0.12
DANN	Benign	0.78
DEOGEN2	Benign	0.0032	T
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.1	L
PhyloP100		-1.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.20
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.52	P
Vest4		0.31
MutPred		0.52		Gain of catalytic residue at V89 (P = 0.011);
MVP		0.12
MPC		0.050
ClinPred		0.052	T
GERP RS		-9.0
Varity_R		0.10
gMVP		0.35
Mutation Taster		=99/1	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: rs758401189; hg19: chrX-150789473;