rs41276027

Variant names:

• chr7-37894545-A-T
• rs41276027
• NM_016616.5:c.1479A>T

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.1479A>T​(p.Ile493Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 1,606,362 control chromosomes in the GnomAD database, including 88,552 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6052 hom., cov: 32)
  • Exomes 𝑓: 0.33 (82500 hom.)
• Consequence: NME8 NM_016616.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.337
• 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: 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=-0.97).
• BP6: Variant 7-37894545-A-T is Benign according to our data. Variant chr7-37894545-A-T is described in ClinVar as Benign. ClinVar VariationId is 164805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.337 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.357 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.1479A>T	p.Ile493Ile	synonymous	Exon 16 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.1479A>T	p.Ile493Ile	synonymous	Exon 16 of 18	ENSP00000199447.4	Q8N427
	NME8	ENST00000440017.5	TSL:1	c.1479A>T	p.Ile493Ile	synonymous	Exon 15 of 16	ENSP00000397063.1	Q8N427
	ENSG00000290149	ENST00000476620.1	TSL:4	c.-38+37200A>T		intron	N/A	ENSP00000425858.1	D6RIH7

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38047 AN: 151874 Hom.: 6051 Cov.: 32

Gnomad AFR AF: 0.0676

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.276

GnomAD2 exomes AF: 0.273 AC: 68343 AN: 250598 AF XY: 0.273

Gnomad AFR exome AF: 0.0591

Gnomad AMR exome AF: 0.237

Gnomad ASJ exome AF: 0.297

Gnomad EAS exome AF: 0.128

Gnomad FIN exome AF: 0.327

Gnomad NFE exome AF: 0.353

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.328 AC: 476342 AN: 1454370 Hom.: 82500 Cov.: 34 AF XY: 0.324 AC XY: 234386 AN XY: 723898

African (AFR) AF: 0.0524 AC: 1750 AN: 33394

American (AMR) AF: 0.242 AC: 10816 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 7809 AN: 26032

East Asian (EAS) AF: 0.157 AC: 6231 AN: 39602

South Asian (SAS) AF: 0.167 AC: 14386 AN: 86120

European-Finnish (FIN) AF: 0.333 AC: 17798 AN: 53376

Middle Eastern (MID) AF: 0.261 AC: 1497 AN: 5728

European-Non Finnish (NFE) AF: 0.359 AC: 397308 AN: 1105410

Other (OTH) AF: 0.312 AC: 18747 AN: 60104

GnomAD4 genome AF: 0.250 AC: 38037 AN: 151992 Hom.: 6052 Cov.: 32 AF XY: 0.246 AC XY: 18266 AN XY: 74284

African (AFR) AF: 0.0674 AC: 2800 AN: 41544

American (AMR) AF: 0.247 AC: 3773 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 1061 AN: 3470

East Asian (EAS) AF: 0.137 AC: 706 AN: 5166

South Asian (SAS) AF: 0.162 AC: 780 AN: 4818

European-Finnish (FIN) AF: 0.322 AC: 3396 AN: 10542

Middle Eastern (MID) AF: 0.260 AC: 76 AN: 292

European-Non Finnish (NFE) AF: 0.361 AC: 24495 AN: 67888

Other (OTH) AF: 0.272 AC: 575 AN: 2112

Alfa AF: 0.328 Hom.: 2807

Bravo AF: 0.240

Asia WGS AF: 0.152 AC: 528 AN: 3474

EpiCase AF: 0.350

EpiControl AF: 0.343

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.41
DANN	Benign	0.50
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41276027; hg19: chr7-37934147; COSMIC: COSV52250933; COSMIC: COSV52250933;