15-41387308-CAAAAAAAAAA-CAAAAAAAAA

Variant names:

• chr15-41387308-CA-C
• rs751327964
• ENST00000560978.2:c.*135delT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The ENST00000560978.2(NDUFAF1):​c.*135delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0062 (1 hom., cov: 30)
  • Exomes 𝑓: 0.23 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NDUFAF1 ENST00000560978.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.231
• Publications: 1 publications found

Genes affected

NDUFAF1 (HGNC:18828): (NADH:ubiquinone oxidoreductase complex assembly factor 1) This gene encodes a complex I assembly factor protein. Complex I (NADH-ubiquinone oxidoreductase) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. The encoded protein is required for assembly of complex I, and mutations in this gene are a cause of mitochondrial complex I deficiency. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 19. [provided by RefSeq, Dec 2011]

NDUFAF1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency, nuclear type 11

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 15-41387308-CA-C is Benign according to our data. Variant chr15-41387308-CA-C is described in ClinVar as Benign. ClinVar VariationId is 1179686.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000560978.2. 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
	NDUFAF1	NM_016013.4	MANE Select	c.*135delT		downstream_gene	N/A	NP_057097.2
	NDUFAF1	NM_001437486.1		c.*135delT		downstream_gene	N/A	NP_001424415.1
	NDUFAF1	NM_001437487.1		c.*135delT		downstream_gene	N/A	NP_001424416.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF1	ENST00000560978.2	TSL:3	c.*135delT		3_prime_UTR	Exon 5 of 5	ENSP00000453944.2	Q9Y375
	NDUFAF1	ENST00000260361.9	TSL:1 MANE Select	c.*135delT		downstream_gene	N/A	ENSP00000260361.4	Q9Y375
	NDUFAF1	ENST00000559127.5	TSL:1	n.*587delT		downstream_gene	N/A	ENSP00000453027.1	H0YL22

Frequencies

GnomAD3 genomes AF: 0.00613 AC: 409 AN: 66710 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.00253

Gnomad AMR AF: 0.00551

Gnomad ASJ AF: 0.00166

Gnomad EAS AF: 0.00134

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.0213

Gnomad NFE AF: 0.00279

Gnomad OTH AF: 0.00111

GnomAD2 exomes AF: 0.295 AC: 12260 AN: 41530 AF XY: 0.288

Gnomad AFR exome AF: 0.303

Gnomad AMR exome AF: 0.329

Gnomad ASJ exome AF: 0.275

Gnomad EAS exome AF: 0.326

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.290

Gnomad OTH exome AF: 0.306

GnomAD4 exome AF: 0.227 AC: 109621 AN: 483418 Hom.: 0 Cov.: 0 AF XY: 0.228 AC XY: 58078 AN XY: 255084

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

African (AFR) AF: 0.227 AC: 2746 AN: 12082

American (AMR) AF: 0.238 AC: 4225 AN: 17716

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 2916 AN: 12818

East Asian (EAS) AF: 0.246 AC: 6175 AN: 25152

South Asian (SAS) AF: 0.237 AC: 10514 AN: 44372

European-Finnish (FIN) AF: 0.223 AC: 5397 AN: 24168

Middle Eastern (MID) AF: 0.238 AC: 429 AN: 1804

European-Non Finnish (NFE) AF: 0.223 AC: 71485 AN: 320840

Other (OTH) AF: 0.234 AC: 5734 AN: 24466

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00616 AC: 411 AN: 66728 Hom.: 1 Cov.: 30 AF XY: 0.00624 AC XY: 194 AN XY: 31112

African (AFR) AF: 0.0115 AC: 202 AN: 17556

American (AMR) AF: 0.00568 AC: 33 AN: 5812

Ashkenazi Jewish (ASJ) AF: 0.00166 AC: 3 AN: 1802

East Asian (EAS) AF: 0.00135 AC: 3 AN: 2228

South Asian (SAS) AF: 0.00500 AC: 11 AN: 2200

European-Finnish (FIN) AF: 0.0195 AC: 62 AN: 3180

Middle Eastern (MID) AF: 0.0227 AC: 2 AN: 88

European-Non Finnish (NFE) AF: 0.00280 AC: 91 AN: 32552

Other (OTH) AF: 0.00328 AC: 3 AN: 914

Alfa AF: 0.00725 Hom.: 1

ClinVar

ClinVar submissions as Germline

Significance: 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
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs751327964; hg19: chr15-41679506; COSMIC: COSV52974957;