chr10-122412965-C-T

Variant names:

• chr10-122412965-C-T
• rs144243343
• NM_001001974.4:c.388C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001001974.4(PLEKHA1):​c.388C>T​(p.Arg130Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,613,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R130G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: PLEKHA1 NM_001001974.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.20
• Publications: 1 publications found

Genes affected

PLEKHA1 (HGNC:14335): (pleckstrin homology domain containing A1) This gene encodes a pleckstrin homology domain-containing adapter protein. The encoded protein is localized to the plasma membrane where it specifically binds phosphatidylinositol 3,4-bisphosphate. This protein may be involved in the formation of signaling complexes in the plasma membrane. Polymorphisms in this gene are associated with age-related macular degeneration. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 5.[provided by RefSeq, Sep 2010]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.037849784).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001974.4. 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
	PLEKHA1	NM_001001974.4	MANE Select	c.388C>T	p.Arg130Cys	missense	Exon 6 of 12	NP_001001974.1	Q9HB21-1
	PLEKHA1	NM_001377230.1		c.388C>T	p.Arg130Cys	missense	Exon 7 of 13	NP_001364159.1	Q9HB21-1
	PLEKHA1	NM_001377231.1		c.388C>T	p.Arg130Cys	missense	Exon 9 of 15	NP_001364160.1	Q9HB21-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHA1	ENST00000368990.8	TSL:1 MANE Select	c.388C>T	p.Arg130Cys	missense	Exon 6 of 12	ENSP00000357986.3	Q9HB21-1
	PLEKHA1	ENST00000392799.7	TSL:1	c.388C>T	p.Arg130Cys	missense	Exon 7 of 13	ENSP00000376547.3	Q9HB21-1
	PLEKHA1	ENST00000433307.2	TSL:1	c.388C>T	p.Arg130Cys	missense	Exon 5 of 11	ENSP00000394416.1	Q9HB21-1

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000677 AC: 17 AN: 251120 AF XY: 0.0000442

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1461216 Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 26 AN XY: 726932

African (AFR) AF: 0.000179 AC: 6 AN: 33452

American (AMR) AF: 0.000157 AC: 7 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39664

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111548

Other (OTH) AF: 0.000149 AC: 9 AN: 60372

GnomAD4 genome AF: 0.000178 AC: 27 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74260

African (AFR) AF: 0.000386 AC: 16 AN: 41406

American (AMR) AF: 0.000524 AC: 8 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68002

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000408

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.0043
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.099
Sift	Benign	0.074	T
Sift4G	Benign	0.063	T
Polyphen		0.0060	B
Vest4		0.26
MVP		0.26
MPC		0.49
ClinPred		0.019	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.061
gMVP		0.28
Mutation Taster		=87/13	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: rs144243343; hg19: chr10-124172481;