NM_016616.5:c.1603T>C

Variant names:

• chr7-37896928-T-C
• rs3213975
• NM_016616.5:c.1603T>C

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.1603T>C​(p.Leu535Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,613,196 control chromosomes in the GnomAD database, including 44,033 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (3886 hom., cov: 31)
  • Exomes 𝑓: 0.23 (40147 hom.)
• Consequence: NME8 NM_016616.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.314
• Publications: 20 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000290149 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-37896928-T-C is Benign according to our data. Variant chr7-37896928-T-C is described in ClinVar as Benign. ClinVar VariationId is 164806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.314 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.232 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NME8	NM_016616.5	MANE Select	c.1603T>C	p.Leu535Leu	synonymous	Exon 17 of 18	NP_057700.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NME8	ENST00000199447.9	TSL:1 MANE Select	c.1603T>C	p.Leu535Leu	synonymous	Exon 17 of 18	ENSP00000199447.4	Q8N427
	NME8	ENST00000440017.5	TSL:1	c.1603T>C	p.Leu535Leu	synonymous	Exon 16 of 16	ENSP00000397063.1	Q8N427
	ENSG00000290149	ENST00000476620.1	TSL:4	c.-38+39583T>C		intron	N/A	ENSP00000425858.1	D6RIH7

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34381 AN: 151760 Hom.: 3883 Cov.: 31

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.220

GnomAD2 exomes AF: 0.242 AC: 60776 AN: 251196 AF XY: 0.244

Gnomad AFR exome AF: 0.202

Gnomad AMR exome AF: 0.274

Gnomad ASJ exome AF: 0.267

Gnomad EAS exome AF: 0.231

Gnomad FIN exome AF: 0.250

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.238

GnomAD4 exome AF: 0.233 AC: 340358 AN: 1461318 Hom.: 40147 Cov.: 35 AF XY: 0.233 AC XY: 169736 AN XY: 726982

African (AFR) AF: 0.205 AC: 6868 AN: 33448

American (AMR) AF: 0.266 AC: 11896 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 6851 AN: 26126

East Asian (EAS) AF: 0.224 AC: 8890 AN: 39694

South Asian (SAS) AF: 0.228 AC: 19676 AN: 86246

European-Finnish (FIN) AF: 0.242 AC: 12907 AN: 53420

Middle Eastern (MID) AF: 0.233 AC: 1343 AN: 5758

European-Non Finnish (NFE) AF: 0.232 AC: 257968 AN: 1111568

Other (OTH) AF: 0.231 AC: 13959 AN: 60368

GnomAD4 genome AF: 0.227 AC: 34408 AN: 151878 Hom.: 3886 Cov.: 31 AF XY: 0.227 AC XY: 16847 AN XY: 74200

African (AFR) AF: 0.206 AC: 8515 AN: 41410

American (AMR) AF: 0.227 AC: 3463 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 923 AN: 3466

East Asian (EAS) AF: 0.221 AC: 1137 AN: 5138

South Asian (SAS) AF: 0.226 AC: 1086 AN: 4808

European-Finnish (FIN) AF: 0.244 AC: 2577 AN: 10560

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.235 AC: 15977 AN: 67924

Other (OTH) AF: 0.220 AC: 463 AN: 2104

Alfa AF: 0.237 Hom.: 7089

Bravo AF: 0.229

Asia WGS AF: 0.229 AC: 796 AN: 3478

EpiCase AF: 0.239

EpiControl AF: 0.245

ClinVar

ClinVar submissions

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	-0.84
CADD	Benign	0.45
DANN	Benign	0.51
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs3213975; hg19: chr7-37936530; COSMIC: COSV52247394;