chr19-14566252-T-A

Variant names:

• chr19-14566252-T-A
• rs768959190
• NM_004146.6:c.295A>T

Variant summary

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

The NM_004146.6(NDUFB7):​c.295A>T​(p.Met99Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDUFB7 NM_004146.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.70
• Publications: 0 publications found

Genes affected

NDUFB7 (HGNC:7702): (NADH:ubiquinone oxidoreductase subunit B7) The protein encoded by this gene is a subunit of the multisubunit NADH:ubiquinone oxidoreductase (complex I). Mammalian complex I is composed of 45 different subunits. It is located at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. [provided by RefSeq, Jul 2008]

NDUFB7 Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 39

  Inheritance: AR Classification: LIMITED Submitted by: G2P

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=0.38310063).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004146.6. 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
	NDUFB7	NM_004146.6	MANE Select	c.295A>T	p.Met99Leu	missense	Exon 3 of 3	NP_004137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFB7	ENST00000215565.3	TSL:1 MANE Select	c.295A>T	p.Met99Leu	missense	Exon 3 of 3	ENSP00000215565.1	P17568
	NDUFB7	ENST00000897442.1		c.409A>T	p.Met137Leu	missense	Exon 4 of 4	ENSP00000567501.1
	NDUFB7	ENST00000928508.1		c.334A>T	p.Met112Leu	missense	Exon 4 of 4	ENSP00000598567.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250316 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		3.7
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.17
Sift	Benign	0.084	T
Sift4G	Benign	0.085	T
Polyphen		0.73	P
Vest4		0.35
MutPred		0.59		Gain of methylation at K100 (P = 0.0377)
MVP		0.41
MPC		0.14
ClinPred		0.80	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.85
Mutation Taster		=86/14	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

dbSNP: rs768959190; hg19: chr19-14677064;