chr4-7061167-C-T

Variant names:

• chr4-7061167-C-T
• rs146608974
• NM_025196.4:c.349G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_025196.4(GRPEL1):​c.349G>A​(p.Val117Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000637 in 1,613,556 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (1 hom.)
• Consequence: GRPEL1 NM_025196.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.14
• Publications: 8 publications found

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

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011043102).
• BP6: Variant 4-7061167-C-T is Benign according to our data. Variant chr4-7061167-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2654632.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025196.4. 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
	GRPEL1	NM_025196.4	MANE Select	c.349G>A	p.Val117Ile	missense	Exon 4 of 4	NP_079472.1	Q9HAV7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRPEL1	ENST00000264954.5	TSL:1 MANE Select	c.349G>A	p.Val117Ile	missense	Exon 4 of 4	ENSP00000264954.4	Q9HAV7
	GRPEL1	ENST00000869293.1		c.358G>A	p.Val120Ile	missense	Exon 4 of 4	ENSP00000539352.1
	GRPEL1	ENST00000869291.1		c.346G>A	p.Val116Ile	missense	Exon 4 of 4	ENSP00000539350.1

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 353 AN: 152186 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00770

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000929 AC: 233 AN: 250746 AF XY: 0.000804

Gnomad AFR exome AF: 0.00837

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00549

Gnomad EAS exome AF: 0.000870

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000970

Gnomad OTH exome AF: 0.000983

GnomAD4 exome AF: 0.000455 AC: 665 AN: 1461252 Hom.: 1 Cov.: 30 AF XY: 0.000436 AC XY: 317 AN XY: 726944

African (AFR) AF: 0.00928 AC: 310 AN: 33414

American (AMR) AF: 0.000515 AC: 23 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00521 AC: 136 AN: 26086

East Asian (EAS) AF: 0.000781 AC: 31 AN: 39692

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.0000792 AC: 88 AN: 1111746

Other (OTH) AF: 0.00101 AC: 61 AN: 60356

GnomAD4 genome AF: 0.00238 AC: 363 AN: 152304 Hom.: 3 Cov.: 33 AF XY: 0.00235 AC XY: 175 AN XY: 74486

African (AFR) AF: 0.00792 AC: 329 AN: 41548

American (AMR) AF: 0.000588 AC: 9 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68032

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00104 Hom.: 6

Bravo AF: 0.00280

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000972 AC: 118

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.73
DEOGEN2	Benign	0.0090	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.78	N
PhyloP100		3.1
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.047
MVP		0.12
MPC		0.18
ClinPred		0.00038	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.021
gMVP		0.18
Mutation Taster		=98/2	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: rs146608974; hg19: chr4-7062894; COSMIC: COSV53827008; COSMIC: COSV53827008;