NM_016616.5:c.271-27C>T

Variant names:

• chr7-37862001-C-T
• rs117149381
• NM_016616.5:c.271-27C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016616.5(NME8):​c.271-27C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0209 in 1,407,586 control chromosomes in the GnomAD database, including 392 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (37 hom., cov: 32)
  • Exomes 𝑓: 0.021 (355 hom.)
• Consequence: NME8 NM_016616.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:4 O:1
• Conservation: PhyloP100: 0.124
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-37862001-C-T is Benign according to our data. Variant chr7-37862001-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 3257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0169 (2570/152262) while in subpopulation NFE AF = 0.027 (1836/68018). AF 95% confidence interval is 0.026. There are 37 homozygotes in GnomAd4. There are 1192 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 AR,AD gene

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.271-27C>T		intron	N/A	NP_057700.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NME8	ENST00000199447.9	TSL:1 MANE Select	c.271-27C>T		intron	N/A	ENSP00000199447.4
	NME8	ENST00000440017.5	TSL:1	c.271-27C>T		intron	N/A	ENSP00000397063.1
	ENSG00000290149	ENST00000476620.1	TSL:4	c.-38+4656C>T		intron	N/A	ENSP00000425858.1

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2570 AN: 152144 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.00355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.0278

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0179 AC: 4480 AN: 250674 AF XY: 0.0180

Gnomad AFR exome AF: 0.00327

Gnomad AMR exome AF: 0.00866

Gnomad ASJ exome AF: 0.0174

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0323

Gnomad NFE exome AF: 0.0262

Gnomad OTH exome AF: 0.0216

GnomAD4 exome AF: 0.0214 AC: 26846 AN: 1255324 Hom.: 355 Cov.: 18 AF XY: 0.0212 AC XY: 13471 AN XY: 635390

African (AFR) AF: 0.00429 AC: 126 AN: 29364

American (AMR) AF: 0.00963 AC: 428 AN: 44464

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 423 AN: 24800

East Asian (EAS) AF: 0.0000516 AC: 2 AN: 38740

South Asian (SAS) AF: 0.00542 AC: 444 AN: 81982

European-Finnish (FIN) AF: 0.0373 AC: 1988 AN: 53306

Middle Eastern (MID) AF: 0.0201 AC: 108 AN: 5382

European-Non Finnish (NFE) AF: 0.0242 AC: 22331 AN: 923770

Other (OTH) AF: 0.0186 AC: 996 AN: 53516

GnomAD4 genome AF: 0.0169 AC: 2570 AN: 152262 Hom.: 37 Cov.: 32 AF XY: 0.0160 AC XY: 1192 AN XY: 74432

African (AFR) AF: 0.00354 AC: 147 AN: 41572

American (AMR) AF: 0.0109 AC: 166 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 63 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00498 AC: 24 AN: 4818

European-Finnish (FIN) AF: 0.0278 AC: 295 AN: 10604

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0270 AC: 1836 AN: 68018

Other (OTH) AF: 0.0152 AC: 32 AN: 2110

Alfa AF: 0.0200 Hom.: 24

Bravo AF: 0.0148

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	1	Primary ciliary dyskinesia 6 (3)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.78
DANN	Benign	0.65
PhyloP100		0.12
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: rs117149381; hg19: chr7-37901603;