10-34119614-G-A

Variant names:

• chr10-34119614-G-A
• rs765436377
• NM_001184785.2:c.3667C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001184785.2(PARD3):​c.3667C>T​(p.Arg1223Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000475 in 1,599,022 control chromosomes in the GnomAD database, including 1 homozygotes. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000048 (1 hom.)
• Consequence: PARD3 NM_001184785.2 missense, splice_region
• Scores: Splicing: ADA: 0.01011
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54
• Publications: 5 publications found

Genes affected

PARD3 (HGNC:16051): (par-3 family cell polarity regulator) This gene encodes a member of the PARD protein family. PARD family members interact with other PARD family members and other proteins; they affect asymmetrical cell division and direct polarized cell growth. Multiple alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARD3	NM_001184785.2	c.3667C>T	p.Arg1223Trp	missense_variant, splice_region_variant	Exon 24 of 25	ENST00000374788.8	NP_001171714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARD3	ENST00000374788.8	c.3667C>T	p.Arg1223Trp	missense_variant, splice_region_variant	Exon 24 of 25	1	NM_001184785.2	ENSP00000363920.3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000179 AC: 43 AN: 240174 AF XY: 0.000107

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00123

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: 0.000171

GnomAD4 exome AF: 0.0000484 AC: 70 AN: 1446704 Hom.: 1 Cov.: 31 AF XY: 0.0000348 AC XY: 25 AN XY: 718376

African (AFR) AF: 0.00 AC: 0 AN: 33068

American (AMR) AF: 0.00127 AC: 56 AN: 44148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25842

East Asian (EAS) AF: 0.00 AC: 0 AN: 39214

South Asian (SAS) AF: 0.0000587 AC: 5 AN: 85186

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000363 AC: 4 AN: 1102214

Other (OTH) AF: 0.0000672 AC: 4 AN: 59542

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74480

African (AFR) AF: 0.0000241 AC: 1 AN: 41570

American (AMR) AF: 0.000261 AC: 4 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3676C>T (p.R1226W) alteration is located in exon 24 (coding exon 24) of the PARD3 gene. This alteration results from a C to T substitution at nucleotide position 3676, causing the arginine (R) at amino acid position 1226 to be replaced by a tryptophan (W). 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	Pathogenic	0.90
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	.;.;T;.;.;.;.;.
Eigen	Benign	0.033
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.97	.;.;L;.;.;.;.;.
PhyloP100		1.5
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.0	D;D;D;D;D;D;D;D
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;D;D;D;.
Vest4		0.86
MutPred		0.21		.;.;Loss of loop (P = 0.0389);.;.;.;.;.;
MVP		0.67
MPC		0.47
ClinPred		0.34	T
GERP RS		-2.0
Varity_R		0.61
gMVP		0.49
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.010
dbscSNV1_RF	Benign	0.46
SpliceAI score (max)		0.010		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: rs765436377; hg19: chr10-34408542;