rs2249451

Variant names:

• chr7-37861979-G-A
• rs2249451
• NM_016616.5:c.271-49G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-37861979-G-A
• chr7-37861979-G-C
• chr7-37861979-G-T

Variant summary

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

The NM_016616.5(NME8):​c.271-49G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.918 in 1,142,696 control chromosomes in the GnomAD database, including 483,977 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.92 (64209 hom., cov: 32)
  • Exomes 𝑓: 0.92 (419768 hom.)
• Consequence: NME8 NM_016616.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.767
• 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=-0.93).
• BP6: Variant 7-37861979-G-A is Benign according to our data. Variant chr7-37861979-G-A is described in ClinVar as Benign. ClinVar VariationId is 260759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.942 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.271-49G>A		intron	N/A	NP_057700.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NME8	ENST00000199447.9	TSL:1 MANE Select	c.271-49G>A		intron	N/A	ENSP00000199447.4
	NME8	ENST00000440017.5	TSL:1	c.271-49G>A		intron	N/A	ENSP00000397063.1
	ENSG00000290149	ENST00000476620.1	TSL:4	c.-38+4634G>A		intron	N/A	ENSP00000425858.1

Frequencies

GnomAD3 genomes AF: 0.916 AC: 139411 AN: 152122 Hom.: 64161 Cov.: 32

Gnomad AFR AF: 0.921

Gnomad AMI AF: 0.958

Gnomad AMR AF: 0.902

Gnomad ASJ AF: 0.967

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.817

Gnomad FIN AF: 0.844

Gnomad MID AF: 0.952

Gnomad NFE AF: 0.948

Gnomad OTH AF: 0.926

GnomAD2 exomes AF: 0.886 AC: 221766 AN: 250426 AF XY: 0.887

Gnomad AFR exome AF: 0.917

Gnomad AMR exome AF: 0.813

Gnomad ASJ exome AF: 0.964

Gnomad EAS exome AF: 0.690

Gnomad FIN exome AF: 0.861

Gnomad NFE exome AF: 0.947

Gnomad OTH exome AF: 0.913

GnomAD4 exome AF: 0.918 AC: 909538 AN: 990454 Hom.: 419768 Cov.: 13 AF XY: 0.916 AC XY: 471001 AN XY: 513960

African (AFR) AF: 0.919 AC: 22350 AN: 24328

American (AMR) AF: 0.825 AC: 36402 AN: 44130

Ashkenazi Jewish (ASJ) AF: 0.963 AC: 22320 AN: 23172

East Asian (EAS) AF: 0.710 AC: 26626 AN: 37506

South Asian (SAS) AF: 0.831 AC: 63728 AN: 76652

European-Finnish (FIN) AF: 0.867 AC: 46084 AN: 53174

Middle Eastern (MID) AF: 0.950 AC: 4621 AN: 4862

European-Non Finnish (NFE) AF: 0.948 AC: 646275 AN: 681780

Other (OTH) AF: 0.917 AC: 41132 AN: 44850

GnomAD4 genome AF: 0.916 AC: 139518 AN: 152242 Hom.: 64209 Cov.: 32 AF XY: 0.908 AC XY: 67601 AN XY: 74434

African (AFR) AF: 0.921 AC: 38278 AN: 41542

American (AMR) AF: 0.902 AC: 13786 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.967 AC: 3357 AN: 3470

East Asian (EAS) AF: 0.693 AC: 3582 AN: 5170

South Asian (SAS) AF: 0.817 AC: 3945 AN: 4828

European-Finnish (FIN) AF: 0.844 AC: 8939 AN: 10590

Middle Eastern (MID) AF: 0.952 AC: 280 AN: 294

European-Non Finnish (NFE) AF: 0.948 AC: 64518 AN: 68034

Other (OTH) AF: 0.926 AC: 1959 AN: 2116

Alfa AF: 0.935 Hom.: 31993

Bravo AF: 0.918

Asia WGS AF: 0.762 AC: 2652 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.1
DANN	Benign	0.29
PhyloP100		0.77
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: rs2249451; hg19: chr7-37901581; COSMIC: COSV52247858;