rs77216981

Variant names:

• chr2-239957769-C-T
• rs77216981
• NM_004544.4:c.*3349G>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.*3349G>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 0.0262 in 152,294 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (89 hom., cov: 33)
  • Exomes 𝑓: 0.063 (0 hom.)
• Consequence: NDUFA10 NM_004544.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.71
• Publications: 3 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=-0.88).
• BP6: Variant 2-239957769-C-T is Benign according to our data. Variant chr2-239957769-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 335154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0798 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.*3349G>A		3_prime_UTR	Exon 10 of 10	NP_004535.1	O95299-1
	NDUFA10	NM_001322020.2		c.*3354G>A		3_prime_UTR	Exon 9 of 9	NP_001308949.1	A0A7I2V438
	NDUFA10	NR_136155.2		n.7500G>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.*3349G>A		3_prime_UTR	Exon 10 of 10	ENSP00000252711.2	O95299-1
	NDUFA10	ENST00000676491.1		c.*1182G>A		3_prime_UTR	Exon 10 of 10	ENSP00000504528.1	A0A7I2V5B2
	NDUFA10	ENST00000678455.1		c.*3349G>A		3_prime_UTR	Exon 10 of 10	ENSP00000504395.1	A0A7I2V594

Frequencies

GnomAD3 genomes AF: 0.0262 AC: 3988 AN: 152160 Hom.: 90 Cov.: 33

Gnomad AFR AF: 0.00690

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0223

Gnomad ASJ AF: 0.0608

Gnomad EAS AF: 0.0870

Gnomad SAS AF: 0.0665

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0320

Gnomad OTH AF: 0.0268

GnomAD4 exome AF: 0.0625 AC: 1 AN: 16 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 14

⚠️ 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) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0714 AC: 1 AN: 14

Other (OTH) AF: 0.00 AC: 0 AN: 2

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0262 AC: 3985 AN: 152278 Hom.: 89 Cov.: 33 AF XY: 0.0263 AC XY: 1957 AN XY: 74458

African (AFR) AF: 0.00691 AC: 287 AN: 41556

American (AMR) AF: 0.0222 AC: 340 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0608 AC: 211 AN: 3470

East Asian (EAS) AF: 0.0864 AC: 447 AN: 5174

South Asian (SAS) AF: 0.0666 AC: 321 AN: 4820

European-Finnish (FIN) AF: 0.00791 AC: 84 AN: 10618

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0320 AC: 2179 AN: 68028

Other (OTH) AF: 0.0270 AC: 57 AN: 2114

Alfa AF: 0.0318 Hom.: 134

Bravo AF: 0.0264

Asia WGS AF: 0.0970 AC: 337 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	-0.88
CADD	Benign	5.0
DANN	Benign	0.80
PhyloP100		1.7
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: rs77216981; hg19: chr2-240897186;