4-139292563-T-C

Variant names:

• chr4-139292563-T-C
• NM_001184989.2:c.218A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001184989.2(NDUFC1):​c.218A>G​(p.Asn73Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,411,870 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: NDUFC1 NM_001184989.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.65
• Publications: 0 publications found

Genes affected

NDUFC1 (HGNC:7705): (NADH:ubiquinone oxidoreductase subunit C1) The encoded protein is a subunit of the NADH:ubiquinone oxidoreductase (complex I), the first enzyme complex in the electron transport chain located in the inner mitochondrial membrane. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26619935).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001184989.2. 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
	NDUFC1	NM_001184989.2	MANE Select	c.218A>G	p.Asn73Ser	missense	Exon 5 of 6	NP_001171918.1	O43677
	NDUFC1	NM_001184986.1		c.218A>G	p.Asn73Ser	missense	Exon 5 of 6	NP_001171915.1	O43677
	NDUFC1	NM_001184987.1		c.218A>G	p.Asn73Ser	missense	Exon 4 of 5	NP_001171916.1	O43677

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFC1	ENST00000394223.2	TSL:3 MANE Select	c.218A>G	p.Asn73Ser	missense	Exon 5 of 6	ENSP00000377770.1	O43677
	NDUFC1	ENST00000505036.5	TSL:1	c.218A>G	p.Asn73Ser	missense	Exon 4 of 5	ENSP00000421195.1	O43677
	NDUFC1	ENST00000394228.5	TSL:2	c.218A>G	p.Asn73Ser	missense	Exon 5 of 6	ENSP00000377775.1	O43677

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1411870 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 704148

African (AFR) AF: 0.00 AC: 0 AN: 32254

American (AMR) AF: 0.00 AC: 0 AN: 42822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25656

East Asian (EAS) AF: 0.00 AC: 0 AN: 38896

South Asian (SAS) AF: 0.00 AC: 0 AN: 81920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 9.32e-7 AC: 1 AN: 1072972

Other (OTH) AF: 0.00 AC: 0 AN: 58622

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.73	T
PhyloP100		2.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.065
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.030	D
Polyphen		0.86	P
Vest4		0.30
MutPred		0.20		Gain of disorder (P = 0.093)
MVP		0.37
MPC		0.69
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.052
Mutation Taster		=91/9	polymorphism

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

hg19: chr4-140213717;