16-88731795-C-G

Variant names:

• chr16-88731795-C-G
• rs769506340
• NM_001142864.4:c.3107G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001142864.4(PIEZO1):​c.3107G>C​(p.Arg1036Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,397,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PIEZO1 NM_001142864.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.538

Genes affected

PIEZO1 (HGNC:28993): (piezo type mechanosensitive ion channel component 1 (Er blood group)) The protein encoded by this gene is a mechanically-activated ion channel that links mechanical forces to biological signals. The encoded protein contains 36 transmembrane domains and functions as a homotetramer. Defects in this gene have been associated with dehydrated hereditary stomatocytosis. [provided by RefSeq, Jul 2015]

ENSG00000224888 (HGNC:56095): (HSP90AB1 associated lncRNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO1	NM_001142864.4	c.3107G>C	p.Arg1036Pro	missense_variant	Exon 22 of 51	ENST00000301015.14	NP_001136336.2
HSALR1	NR_103774.1	n.269+347C>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO1	ENST00000301015.14	c.3107G>C	p.Arg1036Pro	missense_variant	Exon 22 of 51	1	NM_001142864.4	ENSP00000301015.9
ENSG00000224888	ENST00000440406.2	n.269+347C>G		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD3 exomes AF: 0.00000646 AC: 1 AN: 154844 Hom.: 0 AF XY: 0.0000121 AC XY: 1 AN XY: 82356

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1397842 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 689422

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T
Eigen	Benign	0.060
Eigen_PC	Benign	-0.073
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.46		Loss of MoRF binding (P = 6e-04);
MVP		0.79
ClinPred		0.88	D
GERP RS		3.3
Varity_R		0.77
gMVP		0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs769506340; hg19: chr16-88798203;