rs4757433

Variant names:

• chr11-16783795-G-A
• rs4757433
• NM_001329630.2:c.3555C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001329630.2(PLEKHA7):​c.3555C>T​(p.Tyr1185Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,512,736 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0029 (13 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (51 hom.)
• Consequence: PLEKHA7 NM_001329630.2 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.25
• Publications: 1 publications found

Genes affected

PLEKHA7 (HGNC:27049): (pleckstrin homology domain containing A7) Enables delta-catenin binding activity. Involved in epithelial cell-cell adhesion; pore complex assembly; and zonula adherens maintenance. Located in several cellular components, including centrosome; nucleoplasm; and zonula adherens. Part of pore complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 11-16783795-G-A is Benign according to our data. Variant chr11-16783795-G-A is described in ClinVar as Benign. ClinVar VariationId is 3044870.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-1.25 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00286 (435/152340) while in subpopulation EAS AF = 0.0388 (201/5174). AF 95% confidence interval is 0.0345. There are 13 homozygotes in GnomAd4. There are 225 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001329630.2. 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
	PLEKHA7	NM_001329630.2	MANE Select	c.3555C>T	p.Tyr1185Tyr	synonymous	Exon 25 of 27	NP_001316559.1	E9PKC0
	PLEKHA7	NM_001410960.1		c.3558C>T	p.Tyr1186Tyr	synonymous	Exon 25 of 27	NP_001397889.1	A0A8V8TMS3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHA7	ENST00000531066.6	TSL:5 MANE Select	c.3555C>T	p.Tyr1185Tyr	synonymous	Exon 25 of 27	ENSP00000435389.1	E9PKC0
	PLEKHA7	ENST00000698836.1		c.3558C>T	p.Tyr1186Tyr	synonymous	Exon 25 of 27	ENSP00000513972.1	A0A8V8TMS3
	PLEKHA7	ENST00000917925.1		c.3399C>T	p.Tyr1133Tyr	synonymous	Exon 24 of 26	ENSP00000587984.1

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 440 AN: 152222 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0390

Gnomad SAS AF: 0.00289

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00735 AC: 841 AN: 114362 AF XY: 0.00590

Gnomad AFR exome AF: 0.000601

Gnomad AMR exome AF: 0.0282

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0309

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000109

Gnomad OTH exome AF: 0.00374

GnomAD4 exome AF: 0.00174 AC: 2370 AN: 1360396 Hom.: 51 Cov.: 31 AF XY: 0.00164 AC XY: 1098 AN XY: 670662

African (AFR) AF: 0.000231 AC: 7 AN: 30300

American (AMR) AF: 0.0251 AC: 813 AN: 32356

Ashkenazi Jewish (ASJ) AF: 0.0000407 AC: 1 AN: 24580

East Asian (EAS) AF: 0.0397 AC: 1323 AN: 33334

South Asian (SAS) AF: 0.000634 AC: 48 AN: 75748

European-Finnish (FIN) AF: 0.000149 AC: 5 AN: 33658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.0000590 AC: 63 AN: 1067802

Other (OTH) AF: 0.00193 AC: 110 AN: 56982

GnomAD4 genome AF: 0.00286 AC: 435 AN: 152340 Hom.: 13 Cov.: 33 AF XY: 0.00302 AC XY: 225 AN XY: 74494

African (AFR) AF: 0.000529 AC: 22 AN: 41584

American (AMR) AF: 0.0112 AC: 172 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.0388 AC: 201 AN: 5174

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4832

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68036

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00232 Hom.: 11

Bravo AF: 0.00456

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PLEKHA7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.024
DANN	Benign	0.54
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4757433; hg19: chr11-16805342; COSMIC: COSV107412208; COSMIC: COSV107412208;