chr6-30914336-G-A

Variant names:

• chr6-30914336-G-A
• rs1017986679
• NM_020442.6:c.-36G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_020442.6(VARS2):​c.-36G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000993 in 1,218,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: VARS2 NM_020442.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.06
• Publications: 0 publications found

Genes affected

VARS2 (HGNC:21642): (valyl-tRNA synthetase 2, mitochondrial) This gene encodes a mitochondrial aminoacyl-tRNA synthetase, which catalyzes the attachment of valine to tRNA(Val) for mitochondrial translation. Mutations in this gene cause combined oxidative phosphorylation deficiency-20, and are also associated with early-onset mitochondrial encephalopathies. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2014]

ENSG00000288473 (HGNC:):

GTF2H4 (HGNC:4658): (general transcription factor IIH subunit 4) Enables RNA polymerase II general transcription initiation factor activity. Involved in transcription by RNA polymerase II. Located in nuclear speck. Part of core TFIIH complex portion of holo TFIIH complex and transcription factor TFIID complex. [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 (BayesDel_noAF=-0.76).
• BP6: Variant 6-30914336-G-A is Benign according to our data. Variant chr6-30914336-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 507743.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00046 (70/152178) while in subpopulation AFR AF = 0.0015 (62/41428). AF 95% confidence interval is 0.0012. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020442.6. 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
	VARS2	NM_020442.6	MANE Select	c.-36G>A		5_prime_UTR	Exon 1 of 30	NP_065175.4
	VARS2	NM_001167734.2		c.-76G>A		5_prime_UTR	Exon 1 of 30	NP_001161206.1	A0A1U9X9B3
	VARS2	NM_001167733.3		c.-228G>A		5_prime_UTR	Exon 1 of 29	NP_001161205.1	Q5ST30-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS2	ENST00000676266.1	MANE Select	c.-36G>A		5_prime_UTR	Exon 1 of 30	ENSP00000502585.1	Q5ST30-1
	VARS2	ENST00000321897.9	TSL:1	c.-501G>A		5_prime_UTR	Exon 1 of 29	ENSP00000316092.5	Q5ST30-1
	VARS2	ENST00000924208.1		c.-41G>A		5_prime_UTR	Exon 1 of 30	ENSP00000594267.1

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.0000478 AC: 51 AN: 1066664 Hom.: 0 Cov.: 19 AF XY: 0.0000415 AC XY: 21 AN XY: 505992

African (AFR) AF: 0.00147 AC: 33 AN: 22502

American (AMR) AF: 0.000467 AC: 4 AN: 8568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14468

East Asian (EAS) AF: 0.00 AC: 0 AN: 26406

South Asian (SAS) AF: 0.000133 AC: 3 AN: 22602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2934

European-Non Finnish (NFE) AF: 0.00000221 AC: 2 AN: 903630

Other (OTH) AF: 0.000207 AC: 9 AN: 43402

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74338

African (AFR) AF: 0.00150 AC: 62 AN: 41428

American (AMR) AF: 0.000392 AC: 6 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.000498 Hom.: 0

Bravo AF: 0.000574

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	12
DANN	Benign	0.82
PhyloP100		1.1
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.5
Mutation Taster		=294/6	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: rs1017986679; hg19: chr6-30882113;