chr12-4654971-G-A

Variant names:

• chr12-4654971-G-A
• rs4147672
• NM_005002.5:c.318+49G>A

Variant summary

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

The NM_005002.5(NDUFA9):​c.318+49G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,473,734 control chromosomes in the GnomAD database, including 51,859 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5770 hom., cov: 32)
  • Exomes 𝑓: 0.26 (46089 hom.)
• Consequence: NDUFA9 NM_005002.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.143
• Publications: 14 publications found

Genes affected

NDUFA9 (HGNC:7693): (NADH:ubiquinone oxidoreductase subunit A9) The encoded protein is a subunit of the hydrophobic protein fraction of the NADH:ubiquinone oxidoreductase (complex I), the first enzyme complex in the electron transport chain located in the inner mitochondrial membrane. A pseudogene has been identified on chromosome 12. [provided by RefSeq, May 2010]

NDUFA9 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: ClinGen, G2P
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency, nuclear type 26

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000255639 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-4654971-G-A is Benign according to our data. Variant chr12-4654971-G-A is described in ClinVar as Benign. ClinVar VariationId is 1243518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005002.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA9	NM_005002.5	MANE Select	c.318+49G>A		intron	N/A	NP_004993.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA9	ENST00000266544.10	TSL:1 MANE Select	c.318+49G>A		intron	N/A	ENSP00000266544.5
	ENSG00000255639	ENST00000648836.1		c.318+49G>A		intron	N/A	ENSP00000497305.1
	NDUFA9	ENST00000396655.6	TSL:1	n.328+49G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41325 AN: 151784 Hom.: 5774 Cov.: 32

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.291

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.367

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.310

GnomAD2 exomes AF: 0.251 AC: 59025 AN: 235540 AF XY: 0.250

Gnomad AFR exome AF: 0.293

Gnomad AMR exome AF: 0.220

Gnomad ASJ exome AF: 0.369

Gnomad EAS exome AF: 0.189

Gnomad FIN exome AF: 0.198

Gnomad NFE exome AF: 0.283

Gnomad OTH exome AF: 0.274

GnomAD4 exome AF: 0.260 AC: 343040 AN: 1321832 Hom.: 46089 Cov.: 18 AF XY: 0.259 AC XY: 171894 AN XY: 663994

African (AFR) AF: 0.293 AC: 8786 AN: 29974

American (AMR) AF: 0.222 AC: 9167 AN: 41290

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 8969 AN: 24468

East Asian (EAS) AF: 0.155 AC: 6038 AN: 38946

South Asian (SAS) AF: 0.170 AC: 13727 AN: 80954

European-Finnish (FIN) AF: 0.201 AC: 10636 AN: 52940

Middle Eastern (MID) AF: 0.371 AC: 2007 AN: 5408

European-Non Finnish (NFE) AF: 0.271 AC: 268755 AN: 992164

Other (OTH) AF: 0.269 AC: 14955 AN: 55688

GnomAD4 genome AF: 0.272 AC: 41343 AN: 151902 Hom.: 5770 Cov.: 32 AF XY: 0.264 AC XY: 19634 AN XY: 74238

African (AFR) AF: 0.291 AC: 12055 AN: 41418

American (AMR) AF: 0.257 AC: 3919 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 1273 AN: 3470

East Asian (EAS) AF: 0.191 AC: 987 AN: 5174

South Asian (SAS) AF: 0.172 AC: 829 AN: 4826

European-Finnish (FIN) AF: 0.198 AC: 2091 AN: 10540

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.282 AC: 19153 AN: 67904

Other (OTH) AF: 0.308 AC: 650 AN: 2112

Alfa AF: 0.281 Hom.: 26591

Bravo AF: 0.277

Asia WGS AF: 0.217 AC: 758 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.6
DANN	Benign	0.35
PhyloP100		-0.14
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: rs4147672; hg19: chr12-4764137; COSMIC: COSV56927506; COSMIC: COSV56927506;