chr5-1801442-C-A

Variant names:

• chr5-1801442-C-A
• rs376509886
• NM_004553.6:c.25C>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_004553.6(NDUFS6):​c.25C>A​(p.Arg9Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. R9R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 36)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NDUFS6 NM_004553.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.282

Genes affected

NDUFS6 (HGNC:7713): (NADH:ubiquinone oxidoreductase subunit S6) This gene encodes a subunit of the NADH:ubiquinone oxidoreductase (complex I), which is the first enzyme complex in the electron transport chain of mitochondria. This complex functions in the transfer of electrons from NADH to the respiratory chain. The subunit encoded by this gene is one of seven subunits in the iron-sulfur protein fraction. Mutations in this gene cause mitochondrial complex I deficiency, a disease that causes a wide variety of clinical disorders, including neonatal disease and adult-onset neurodegenerative disorders.[provided by RefSeq, Oct 2009]

MRPL36 (HGNC:14490): (mitochondrial ribosomal protein L36) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein. A pseudogene corresponding to this gene is found on chromosome 2p. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 5-1801442-C-A is Benign according to our data. Variant chr5-1801442-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 2793891.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.282 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS6	NM_004553.6	c.25C>A	p.Arg9Arg	synonymous_variant	Exon 1 of 4	ENST00000274137.10	NP_004544.1
MRPL36	XM_011514080.3	c.-76G>T		upstream_gene_variant			XP_011512382.1
MRPL36	XM_017009751.3	c.-217G>T		upstream_gene_variant			XP_016865240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS6	ENST00000274137.10	c.25C>A	p.Arg9Arg	synonymous_variant	Exon 1 of 4	1	NM_004553.6	ENSP00000274137.6
NDUFS6	ENST00000469176.1	c.25C>A	p.Arg9Arg	synonymous_variant	Exon 1 of 3	2		ENSP00000422557.1
NDUFS6	ENST00000510329.1	n.22C>A		non_coding_transcript_exon_variant	Exon 1 of 2	3
MRPL36	ENST00000505818.1	c.-121G>T		upstream_gene_variant		3		ENSP00000427152.1

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD3 exomes AF: 0.00000881 AC: 2 AN: 227020 Hom.: 0 AF XY: 0.0000159 AC XY: 2 AN XY: 126058

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000573

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000993

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452784 Hom.: 0 Cov.: 33 AF XY: 0.00000277 AC XY: 2 AN XY: 722728

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 36

Alfa AF: 0.0000254 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.2
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs376509886; hg19: chr5-1801556;