rs567

Variant names:

• chr5-53683267-G-A
• rs567
• NM_002495.4:c.*46G>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 NM_002495.4(NDUFS4):​c.*46G>A variant causes a 3 prime UTR 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 NM_002495.4 3_prime_UTR
• 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 disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002495.4. 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
	NDUFS4	NM_002495.4	MANE Select	c.*46G>A		3_prime_UTR	Exon 5 of 5	NP_002486.1	A0A0S2Z433
	NDUFS4	NM_001318051.2		c.*137G>A		3_prime_UTR	Exon 4 of 4	NP_001304980.1
	NDUFS4	NR_134473.2		n.770G>A		non_coding_transcript_exon	Exon 6 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS4	ENST00000296684.10	TSL:1 MANE Select	c.*46G>A		3_prime_UTR	Exon 5 of 5	ENSP00000296684.5	O43181
	NDUFS4	ENST00000506974.5	TSL:1	n.*350G>A		non_coding_transcript_exon	Exon 6 of 6	ENSP00000425967.1	D6RI09
	NDUFS4	ENST00000506974.5	TSL:1	n.*350G>A		3_prime_UTR	Exon 6 of 6	ENSP00000425967.1	D6RI09

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Leigh syndrome (1)
-	-	1	Mitochondrial complex I deficiency, nuclear type 1 (1)

Computational scores

Source: dbNSFP v4.9

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;