chr2-239957668-C-T

Variant names:

• chr2-239957668-C-T
• rs7573892
• NM_004544.4:c.*3450G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004544.4(NDUFA10):​c.*3450G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 152,122 control chromosomes in the GnomAD database, including 26,672 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26669 hom., cov: 33)
  • Exomes 𝑓: 0.41 (3 hom.)
• Consequence: NDUFA10 NM_004544.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.28
• Publications: 6 publications found

Genes affected

NDUFA10 (HGNC:7684): (NADH:ubiquinone oxidoreductase subunit A10) The protein encoded by this gene is a component of 42 kDa complex I, the first enzyme complex in the electron transport chain of mitochondria. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. A mutation in this gene was found in an individual with Leigh syndrome. [provided by RefSeq, Apr 2016]

NDUFA10 Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 22

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 2-239957668-C-T is Benign according to our data. Variant chr2-239957668-C-T is described in ClinVar as Benign. ClinVar VariationId is 335152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.647 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004544.4. 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
	NDUFA10	NM_004544.4	MANE Select	c.*3450G>A		3_prime_UTR	Exon 10 of 10	NP_004535.1	O95299-1
	NDUFA10	NM_001322020.2		c.*3455G>A		3_prime_UTR	Exon 9 of 9	NP_001308949.1	A0A7I2V438
	NDUFA10	NR_136155.2		n.7601G>A		non_coding_transcript_exon	Exon 9 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA10	ENST00000252711.7	TSL:1 MANE Select	c.*3450G>A		3_prime_UTR	Exon 10 of 10	ENSP00000252711.2	O95299-1
	NDUFA10	ENST00000676491.1		c.*1283G>A		3_prime_UTR	Exon 10 of 10	ENSP00000504528.1	A0A7I2V5B2
	NDUFA10	ENST00000678455.1		c.*3450G>A		3_prime_UTR	Exon 10 of 10	ENSP00000504395.1	A0A7I2V594

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89760 AN: 151970 Hom.: 26647 Cov.: 33

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.529

Gnomad AMR AF: 0.645

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.666

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.647

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.560

Gnomad OTH AF: 0.574

GnomAD4 exome AF: 0.412 AC: 14 AN: 34 Hom.: 3 Cov.: 0 AF XY: 0.545 AC XY: 12 AN XY: 22

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 8 AN: 16

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.333 AC: 4 AN: 12

Other (OTH) AF: 0.333 AC: 2 AN: 6

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00700631), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.591 AC: 89835 AN: 152088 Hom.: 26669 Cov.: 33 AF XY: 0.593 AC XY: 44073 AN XY: 74340

African (AFR) AF: 0.621 AC: 25746 AN: 41458

American (AMR) AF: 0.646 AC: 9873 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.524 AC: 1821 AN: 3472

East Asian (EAS) AF: 0.666 AC: 3438 AN: 5164

South Asian (SAS) AF: 0.447 AC: 2158 AN: 4824

European-Finnish (FIN) AF: 0.647 AC: 6848 AN: 10578

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.560 AC: 38098 AN: 67988

Other (OTH) AF: 0.570 AC: 1199 AN: 2104

Alfa AF: 0.581 Hom.: 10827

Bravo AF: 0.592

Asia WGS AF: 0.572 AC: 1989 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Leigh syndrome (1)
-	-	1	Mitochondrial complex I deficiency, nuclear type 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.15
DANN	Benign	0.48
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs7573892; hg19: chr2-240897085;