chr4-185535375-G-T

Variant names:

• chr4-185535375-G-T
• rs113792127
• NM_014476.6:c.60C>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_014476.6(PDLIM3):​c.60C>A​(p.Gly20Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,608,636 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (10 hom.)
• Consequence: PDLIM3 NM_014476.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.347
• Publications: 3 publications found

Genes affected

PDLIM3 (HGNC:20767): (PDZ and LIM domain 3) The protein encoded by this gene contains a PDZ domain and a LIM domain, indicating that it may be involved in cytoskeletal assembly. In support of this, the encoded protein has been shown to bind the spectrin-like repeats of alpha-actinin-2 and to colocalize with alpha-actinin-2 at the Z lines of skeletal muscle. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. Aberrant alternative splicing of this gene may play a role in myotonic dystrophy. [provided by RefSeq, Apr 2012]

PDLIM3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 4-185535375-G-T is Benign according to our data. Variant chr4-185535375-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 201951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.347 with no splicing effect.
• BS2: High AC in GnomAd4 at 238 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014476.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDLIM3	NM_014476.6	MANE Select	c.60C>A	p.Gly20Gly	synonymous	Exon 1 of 8	NP_055291.2
	PDLIM3	NM_001114107.5		c.60C>A	p.Gly20Gly	synonymous	Exon 1 of 7	NP_001107579.1
	PDLIM3	NM_001257962.2		c.60C>A	p.Gly20Gly	synonymous	Exon 1 of 7	NP_001244891.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDLIM3	ENST00000284767.12	TSL:5 MANE Select	c.60C>A	p.Gly20Gly	synonymous	Exon 1 of 8	ENSP00000284767.8
	PDLIM3	ENST00000284771.7	TSL:1	c.60C>A	p.Gly20Gly	synonymous	Exon 1 of 7	ENSP00000284771.6
	PDLIM3	ENST00000284770.10	TSL:1	c.60C>A	p.Gly20Gly	synonymous	Exon 1 of 5	ENSP00000284770.5

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 238 AN: 152148 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00265

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00139 AC: 338 AN: 242362 AF XY: 0.00141

Gnomad AFR exome AF: 0.000804

Gnomad AMR exome AF: 0.000922

Gnomad ASJ exome AF: 0.000405

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000475

Gnomad NFE exome AF: 0.00253

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.00295 AC: 4301 AN: 1456380 Hom.: 10 Cov.: 31 AF XY: 0.00293 AC XY: 2126 AN XY: 724442

African (AFR) AF: 0.000550 AC: 18 AN: 32746

American (AMR) AF: 0.000971 AC: 43 AN: 44278

Ashkenazi Jewish (ASJ) AF: 0.000578 AC: 15 AN: 25964

East Asian (EAS) AF: 0.00 AC: 0 AN: 39334

South Asian (SAS) AF: 0.000282 AC: 24 AN: 85252

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53194

Middle Eastern (MID) AF: 0.000696 AC: 4 AN: 5748

European-Non Finnish (NFE) AF: 0.00364 AC: 4041 AN: 1109720

Other (OTH) AF: 0.00244 AC: 147 AN: 60144

GnomAD4 genome AF: 0.00156 AC: 238 AN: 152256 Hom.: 1 Cov.: 33 AF XY: 0.00133 AC XY: 99 AN XY: 74438

African (AFR) AF: 0.000722 AC: 30 AN: 41572

American (AMR) AF: 0.00124 AC: 19 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00265 AC: 180 AN: 67990

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00243 Hom.: 0

Bravo AF: 0.00165

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.86
PhyloP100		0.35
PromoterAI		-0.011	Neutral
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: rs113792127; hg19: chr4-186456529; COSMIC: COSV106384689;