rs567

Variant names:

• chr5-53683267-G-A
• rs567
• ENST00000506974.5:n.*350G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-53683267-G-A
• chr5-53683267-G-C
• chr5-53683267-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000506974.5(NDUFS4):​n.*350G>A variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.466 in 1,335,210 control chromosomes in the GnomAD database, including 148,523 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14389 hom., cov: 32)
  • Exomes 𝑓: 0.47 (134134 hom.)
• Consequence: NDUFS4 ENST00000506974.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.79
• Publications: 22 publications found

Genes affected

NDUFS4 (HGNC:7711): (NADH:ubiquinone oxidoreductase subunit S4) This gene encodes an nuclear-encoded accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I, or NADH:ubiquinone oxidoreductase). Complex I removes electrons from NADH and passes them to the electron acceptor ubiquinone. Mutations in this gene can cause mitochondrial complex I deficiencies such as Leigh syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

NDUFS4 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, G2P
• mitochondrial complex I deficiency, nuclear type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mitochondrial complex I deficiency, nuclear type

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 5-53683267-G-A is Benign according to our data. Variant chr5-53683267-G-A is described in ClinVar as Benign. ClinVar VariationId is 353892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS4	NM_002495.4	c.*46G>A		3_prime_UTR_variant	Exon 5 of 5	ENST00000296684.10	NP_002486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS4	ENST00000296684.10	c.*46G>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_002495.4	ENSP00000296684.5

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64128 AN: 151692 Hom.: 14388 Cov.: 32

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.507

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.412

GnomAD2 exomes AF: 0.457 AC: 113385 AN: 248356 AF XY: 0.458

Gnomad AFR exome AF: 0.282

Gnomad AMR exome AF: 0.551

Gnomad ASJ exome AF: 0.387

Gnomad EAS exome AF: 0.270

Gnomad FIN exome AF: 0.509

Gnomad NFE exome AF: 0.479

Gnomad OTH exome AF: 0.467

GnomAD4 exome AF: 0.471 AC: 557935 AN: 1183400 Hom.: 134134 Cov.: 17 AF XY: 0.472 AC XY: 284077 AN XY: 602120

African (AFR) AF: 0.279 AC: 7738 AN: 27726

American (AMR) AF: 0.546 AC: 24057 AN: 44088

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 9414 AN: 24406

East Asian (EAS) AF: 0.281 AC: 10774 AN: 38330

South Asian (SAS) AF: 0.456 AC: 36762 AN: 80622

European-Finnish (FIN) AF: 0.503 AC: 26571 AN: 52876

Middle Eastern (MID) AF: 0.454 AC: 2382 AN: 5250

European-Non Finnish (NFE) AF: 0.486 AC: 417115 AN: 858886

Other (OTH) AF: 0.451 AC: 23122 AN: 51216

GnomAD4 genome AF: 0.423 AC: 64146 AN: 151810 Hom.: 14389 Cov.: 32 AF XY: 0.425 AC XY: 31492 AN XY: 74164

African (AFR) AF: 0.286 AC: 11845 AN: 41376

American (AMR) AF: 0.502 AC: 7639 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1351 AN: 3464

East Asian (EAS) AF: 0.282 AC: 1454 AN: 5162

South Asian (SAS) AF: 0.443 AC: 2133 AN: 4814

European-Finnish (FIN) AF: 0.507 AC: 5344 AN: 10538

Middle Eastern (MID) AF: 0.490 AC: 143 AN: 292

European-Non Finnish (NFE) AF: 0.486 AC: 33000 AN: 67934

Other (OTH) AF: 0.409 AC: 863 AN: 2110

Alfa AF: 0.471 Hom.: 40310

Bravo AF: 0.414

Asia WGS AF: 0.361 AC: 1259 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Leigh syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Mitochondrial complex I deficiency, nuclear type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	16
DANN	Benign	0.87
PhyloP100		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs567; hg19: chr5-52979097; COSMIC: COSV57019229; COSMIC: COSV57019229;