10-100529321-C-A

Variant names:

• chr10-100529321-C-A
• rs1800662
• NM_005004.4:c.212+59G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005004.4(NDUFB8):​c.212+59G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,498,316 control chromosomes in the GnomAD database, including 35,542 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3291 hom., cov: 28)
  • Exomes 𝑓: 0.22 (32251 hom.)
• Consequence: NDUFB8 NM_005004.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.419
• Publications: 14 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 10-100529321-C-A is Benign according to our data. Variant chr10-100529321-C-A is described in ClinVar as Benign. ClinVar VariationId is 1268122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFB8	NM_005004.4	c.212+59G>T		intron_variant	Intron 2 of 4	ENST00000299166.9	NP_004995.1
NDUFB8	NM_001284367.2	c.212+59G>T		intron_variant	Intron 2 of 4		NP_001271296.1
NDUFB8	NM_001284368.1	c.119+59G>T		intron_variant	Intron 2 of 4		NP_001271297.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFB8	ENST00000299166.9	c.212+59G>T		intron_variant	Intron 2 of 4	1	NM_005004.4	ENSP00000299166.4
ENSG00000255339	ENST00000557395.5	n.212+59G>T		intron_variant	Intron 2 of 9	2		ENSP00000456832.1

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31074 AN: 150776 Hom.: 3286 Cov.: 28

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.223

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.206

GnomAD4 exome AF: 0.217 AC: 291780 AN: 1347424 Hom.: 32251 Cov.: 30 AF XY: 0.217 AC XY: 144144 AN XY: 663572

African (AFR) AF: 0.193 AC: 5324 AN: 27642

American (AMR) AF: 0.159 AC: 4029 AN: 25368

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 4319 AN: 21514

East Asian (EAS) AF: 0.184 AC: 6103 AN: 33134

South Asian (SAS) AF: 0.225 AC: 15922 AN: 70766

European-Finnish (FIN) AF: 0.233 AC: 11877 AN: 50988

Middle Eastern (MID) AF: 0.217 AC: 1168 AN: 5390

European-Non Finnish (NFE) AF: 0.219 AC: 231382 AN: 1057462

Other (OTH) AF: 0.211 AC: 11656 AN: 55160

GnomAD4 genome AF: 0.206 AC: 31083 AN: 150892 Hom.: 3291 Cov.: 28 AF XY: 0.206 AC XY: 15205 AN XY: 73638

African (AFR) AF: 0.201 AC: 8236 AN: 41074

American (AMR) AF: 0.177 AC: 2678 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 673 AN: 3456

East Asian (EAS) AF: 0.142 AC: 724 AN: 5092

South Asian (SAS) AF: 0.229 AC: 1087 AN: 4740

European-Finnish (FIN) AF: 0.221 AC: 2294 AN: 10386

Middle Eastern (MID) AF: 0.154 AC: 45 AN: 292

European-Non Finnish (NFE) AF: 0.217 AC: 14719 AN: 67730

Other (OTH) AF: 0.203 AC: 425 AN: 2094

Alfa AF: 0.214 Hom.: 834

Bravo AF: 0.203

Asia WGS AF: 0.191 AC: 664 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 13, 2021

GeneDx

Significance: 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	-0.71
CADD	Benign	5.5
DANN	Benign	0.85
PhyloP100		-0.42
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: rs1800662; hg19: chr10-102289078; COSMIC: COSV54511979; COSMIC: COSV54511979;