8-10765677-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017884.6(PINX1):c.711G>C(p.Glu237Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 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. E237G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PINX1 NM_017884.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.566

Genes affected

PINX1 (HGNC:30046): (PIN2 (TERF1) interacting telomerase inhibitor 1) Enables telomerase RNA binding activity and telomerase inhibitor activity. Involved in several processes, including negative regulation of DNA biosynthetic process; positive regulation of protein localization to nucleolus; and protein localization to organelle. Acts upstream of or within telomere maintenance via telomerase. Located in several cellular components, including chromosomal region; nuclear lumen; and spindle. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12979606).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PINX1	NM_017884.6	c.711G>C	p.Glu237Asp	missense_variant	7/7	ENST00000314787.8
LOC102723313	NR_146188.1	n.341-2723C>G		intron_variant, non_coding_transcript_variant
PINX1	NM_001284356.2	c.*109G>C		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PINX1	ENST00000314787.8	c.711G>C	p.Glu237Asp	missense_variant	7/7	1	NM_017884.6	P2
	ENST00000657150.1	n.174-2723C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

The c.711G>C (p.E237D) alteration is located in exon 7 (coding exon 7) of the PINX1 gene. This alteration results from a G to C substitution at nucleotide position 711, causing the glutamic acid (E) at amino acid position 237 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	6.3
Dann	Benign	0.94
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.074
Sift	Benign	0.053	T
Sift4G	Benign	0.38	T
Polyphen		0.42	B
Vest4		0.15
MutPred		0.10		Loss of loop (P = 0.0112);
MVP		0.47
MPC		0.0017
ClinPred		0.17	T
GERP RS		3.7
Varity_R		0.087
gMVP		0.019

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: rs1801012960; hg19: chr8-10623187;