10-122424896-C-A

Variant names:

• chr10-122424896-C-A
• rs764610376
• NM_001001974.4:c.747C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001001974.4(PLEKHA1):​c.747C>A​(p.Ser249Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,724 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S249S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PLEKHA1 NM_001001974.4 missense, splice_region
• Scores: Splicing: ADA: 0.01266
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.08
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.747C>A	p.Ser249Arg	missense splice_region	Exon 10 of 12	NP_001001974.1	Q9HB21-1
	PLEKHA1	NM_001377230.1		c.747C>A	p.Ser249Arg	missense splice_region	Exon 11 of 13	NP_001364159.1	Q9HB21-1
	PLEKHA1	NM_001377231.1		c.747C>A	p.Ser249Arg	missense splice_region	Exon 13 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.747C>A	p.Ser249Arg	missense splice_region	Exon 10 of 12	ENSP00000357986.3	Q9HB21-1
	PLEKHA1	ENST00000392799.7	TSL:1	c.747C>A	p.Ser249Arg	missense splice_region	Exon 11 of 13	ENSP00000376547.3	Q9HB21-1
	PLEKHA1	ENST00000433307.2	TSL:1	c.747C>A	p.Ser249Arg	missense splice_region	Exon 9 of 11	ENSP00000394416.1	Q9HB21-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453724 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723030

African (AFR) AF: 0.00 AC: 0 AN: 33092

American (AMR) AF: 0.00 AC: 0 AN: 43698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25934

East Asian (EAS) AF: 0.00 AC: 0 AN: 39314

South Asian (SAS) AF: 0.00 AC: 0 AN: 84510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108232

Other (OTH) AF: 0.00 AC: 0 AN: 60004

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.62
Sift	Benign	0.11	T
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.41		Gain of ubiquitination at K247 (P = 0.1047)
MVP		0.84
MPC		0.46
ClinPred		0.98	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.16
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.013
dbscSNV1_RF	Benign	0.18
SpliceAI score (max)		0.030		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: rs764610376; hg19: chr10-124184412;