chr4-7064104-A-G

Position:

• chr4-7064104-A-G

Variant summary

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

The NM_025196.4(GRPEL1):​c.182T>C​(p.Leu61Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GRPEL1 NM_025196.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.395

Genes affected

GRPEL1 (HGNC:19696): (GrpE like 1, mitochondrial) Enables identical protein binding activity and unfolded protein binding activity. Predicted to be involved in protein import into mitochondrial matrix. Located in mitochondrial matrix and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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=0.12942502).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRPEL1	NM_025196.4	c.182T>C	p.Leu61Pro	missense_variant	2/4	ENST00000264954.5	NP_079472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRPEL1	ENST00000264954.5	c.182T>C	p.Leu61Pro	missense_variant	2/4	1	NM_025196.4	ENSP00000264954	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Apr 08, 2024

The c.182T>C (p.L61P) alteration is located in exon 2 (coding exon 2) of the GRPEL1 gene. This alteration results from a T to C substitution at nucleotide position 182, causing the leucine (L) at amino acid position 61 to be replaced by a proline (P). 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	0.26
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.91
DEOGEN2	Benign	0.0090	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.92	L
MutationTaster	Benign	0.92	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.052
Sift	Benign	0.25	T
Sift4G	Benign	0.27	T
Polyphen		0.60	P
Vest4		0.27
MutPred		0.50		Gain of glycosylation at T59 (P = 0.0164);
MVP		0.21
MPC		0.58
ClinPred		0.16	T
GERP RS		3.1
Varity_R		0.11
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-7065831;