rs62001868

Variant names:

• chr7-37876853-A-G
• rs62001868
• NM_016616.5:c.840A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016616.5(NME8):​c.840A>G​(p.Arg280Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0975 in 1,610,984 control chromosomes in the GnomAD database, including 10,365 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1896 hom., cov: 32)
  • Exomes 𝑓: 0.093 (8469 hom.)
• Consequence: NME8 NM_016616.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.316
• Publications: 11 publications found

Genes affected

NME8 (HGNC:16473): (NME/NM23 family member 8) This gene encodes a protein with an N-terminal thioredoxin domain and three C-terminal nucleoside diphosphate kinase (NDK) domains, but the NDK domains are thought to be catalytically inactive. The sea urchin ortholog of this gene encodes a component of sperm outer dynein arms, and the protein is implicated in ciliary function. Mutations in this gene are implicated in primary ciliary dyskinesia type 6.[provided by RefSeq, Nov 2009]

NME8 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• primary ciliary dyskinesia 6

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000290149 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-37876853-A-G is Benign according to our data. Variant chr7-37876853-A-G is described in ClinVar as Benign. ClinVar VariationId is 164802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.316 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016616.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NME8	NM_016616.5	MANE Select	c.840A>G	p.Arg280Arg	synonymous	Exon 12 of 18	NP_057700.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NME8	ENST00000199447.9	TSL:1 MANE Select	c.840A>G	p.Arg280Arg	synonymous	Exon 12 of 18	ENSP00000199447.4
	NME8	ENST00000440017.5	TSL:1	c.840A>G	p.Arg280Arg	synonymous	Exon 11 of 16	ENSP00000397063.1
	ENSG00000290149	ENST00000476620.1	TSL:4	c.-38+19508A>G		intron	N/A	ENSP00000425858.1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 21038 AN: 151980 Hom.: 1887 Cov.: 32

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.0634

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0723

Gnomad OTH AF: 0.104

GnomAD2 exomes AF: 0.122 AC: 30433 AN: 250106 AF XY: 0.123

Gnomad AFR exome AF: 0.238

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.0615

Gnomad EAS exome AF: 0.198

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.0735

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0933 AC: 136071 AN: 1458886 Hom.: 8469 Cov.: 30 AF XY: 0.0965 AC XY: 70030 AN XY: 725802

African (AFR) AF: 0.250 AC: 8351 AN: 33364

American (AMR) AF: 0.112 AC: 4988 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.0590 AC: 1539 AN: 26102

East Asian (EAS) AF: 0.200 AC: 7902 AN: 39446

South Asian (SAS) AF: 0.223 AC: 19192 AN: 85934

European-Finnish (FIN) AF: 0.125 AC: 6644 AN: 53354

Middle Eastern (MID) AF: 0.0929 AC: 534 AN: 5746

European-Non Finnish (NFE) AF: 0.0727 AC: 80739 AN: 1110044

Other (OTH) AF: 0.103 AC: 6182 AN: 60264

GnomAD4 genome AF: 0.138 AC: 21060 AN: 152098 Hom.: 1896 Cov.: 32 AF XY: 0.146 AC XY: 10854 AN XY: 74354

African (AFR) AF: 0.241 AC: 9997 AN: 41440

American (AMR) AF: 0.133 AC: 2026 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0634 AC: 220 AN: 3470

East Asian (EAS) AF: 0.203 AC: 1051 AN: 5172

South Asian (SAS) AF: 0.226 AC: 1091 AN: 4824

European-Finnish (FIN) AF: 0.139 AC: 1471 AN: 10586

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0723 AC: 4918 AN: 67996

Other (OTH) AF: 0.103 AC: 218 AN: 2116

Alfa AF: 0.105 Hom.: 863

Bravo AF: 0.137

Asia WGS AF: 0.205 AC: 713 AN: 3474

EpiCase AF: 0.0701

EpiControl AF: 0.0676

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia (1)
-	-	1	Primary ciliary dyskinesia 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.5
DANN	Benign	0.81
PhyloP100		0.32
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: rs62001868; hg19: chr7-37916455; COSMIC: COSV107213999;