10-100529377-C-T

Variant names:

• chr10-100529377-C-T
• rs371084723
• NM_005004.4:c.212+3G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_005004.4(NDUFB8):​c.212+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,605,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: NDUFB8 NM_005004.4 splice_region, intron
• Scores: Splicing: ADA: 0.001298
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.92
• Publications: 0 publications found

Genes affected

NDUFB8 (HGNC:7703): (NADH:ubiquinone oxidoreductase subunit B8) Involved in mitochondrial respiratory chain complex I assembly. Located in endoplasmic reticulum and mitochondrion. Part of mitochondrial respiratory chain complex I. Implicated in nuclear type mitochondrial complex I deficiency 32. Biomarker of Alzheimer's disease and Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000255339 (HGNC:):

HIF1AN (HGNC:17113): (hypoxia inducible factor 1 subunit alpha inhibitor) Enables several functions, including 2-oxoglutarate-dependent dioxygenase activity; NF-kappaB binding activity; and transition metal ion binding activity. Involved in several processes, including negative regulation of Notch signaling pathway; negative regulation of transcription from RNA polymerase II promoter in response to hypoxia; and protein hydroxylation. Located in cytosol; nucleoplasm; and perinuclear region of cytoplasm. Colocalizes with nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 10-100529377-C-T is Benign according to our data. Variant chr10-100529377-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3036133.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005004.4. 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
	NDUFB8	NM_005004.4	MANE Select	c.212+3G>A		splice_region intron	N/A	NP_004995.1	O95169-1
	NDUFB8	NM_001284367.2		c.212+3G>A		splice_region intron	N/A	NP_001271296.1	O95169-2
	NDUFB8	NM_001284368.1		c.119+3G>A		splice_region intron	N/A	NP_001271297.1	O95169-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFB8	ENST00000299166.9	TSL:1 MANE Select	c.212+3G>A		splice_region intron	N/A	ENSP00000299166.4	O95169-1
	ENSG00000255339	ENST00000557395.5	TSL:2	n.212+3G>A		splice_region intron	N/A	ENSP00000456832.1
	HIF1AN	ENST00000533589.6	TSL:3	c.-164C>T		5_prime_UTR	Exon 1 of 6	ENSP00000433360.2	E9PL41

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152094 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000452 AC: 11 AN: 243604 AF XY: 0.0000605

Gnomad AFR exome AF: 0.000624

Gnomad AMR exome AF: 0.0000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000551 AC: 8 AN: 1452906 Hom.: 0 Cov.: 32 AF XY: 0.00000415 AC XY: 3 AN XY: 722864

African (AFR) AF: 0.000152 AC: 5 AN: 32892

American (AMR) AF: 0.0000240 AC: 1 AN: 41646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25674

East Asian (EAS) AF: 0.00 AC: 0 AN: 39404

South Asian (SAS) AF: 0.00 AC: 0 AN: 85182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109056

Other (OTH) AF: 0.0000333 AC: 2 AN: 59978

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152212 Hom.: 0 Cov.: 31 AF XY: 0.000134 AC XY: 10 AN XY: 74440

African (AFR) AF: 0.000433 AC: 18 AN: 41532

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000650 Hom.: 0

Bravo AF: 0.0000869

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	NDUFB8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.88
PhyloP100		1.9
PromoterAI		0.046	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.032
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: rs371084723; hg19: chr10-102289134;