chr1-225079264-C-G

Variant names:

• chr1-225079264-C-G
• rs3105559
• NM_001367479.1:c.2482C>G

Variant summary

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

The NM_001367479.1(DNAH14):​c.2482C>G​(p.Leu828Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.918 in 1,547,610 control chromosomes in the GnomAD database, including 662,157 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (51748 hom., cov: 31)
  • Exomes 𝑓: 0.93 (610409 hom.)
• Consequence: DNAH14 NM_001367479.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.359
• Publications: 20 publications found

Genes affected

DNAH14 (HGNC:2945): (dynein axonemal heavy chain 14) Dyneins are microtubule-associated motor protein complexes composed of several heavy, light, and intermediate chains. Two major classes of dyneins, axonemal and cytoplasmic, have been identified. DNAH14 is an axonemal dynein heavy chain (DHC) (Vaughan et al., 1996 [PubMed 8812413]).[supplied by OMIM, Mar 2008]

DNAH14 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P
• primary ciliary dyskinesia

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.739373E-7).
• BP6: Variant 1-225079264-C-G is Benign according to our data. Variant chr1-225079264-C-G is described in ClinVar as Benign. ClinVar VariationId is 402645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367479.1. 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
	DNAH14	NM_001367479.1	MANE Select	c.2482C>G	p.Leu828Val	missense	Exon 18 of 86	NP_001354408.1	A0A804HLD3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH14	ENST00000682510.1	MANE Select	c.2482C>G	p.Leu828Val	missense	Exon 18 of 86	ENSP00000508305.1	A0A804HLD3
	DNAH14	ENST00000430092.5	TSL:5	c.2482C>G	p.Leu828Val	missense	Exon 18 of 84	ENSP00000414402.1	Q0VDD8-4
	DNAH14	ENST00000439375.6	TSL:5	c.2482C>G	p.Leu828Val	missense	Exon 17 of 83	ENSP00000392061.2	Q0VDD8-4

Frequencies

GnomAD3 genomes AF: 0.798 AC: 121258 AN: 151968 Hom.: 51730 Cov.: 31

Gnomad AFR AF: 0.474

Gnomad AMI AF: 0.980

Gnomad AMR AF: 0.796

Gnomad ASJ AF: 0.916

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.850

Gnomad FIN AF: 0.967

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.962

Gnomad OTH AF: 0.823

GnomAD2 exomes AF: 0.870 AC: 133093 AN: 153012 AF XY: 0.879

Gnomad AFR exome AF: 0.472

Gnomad AMR exome AF: 0.758

Gnomad ASJ exome AF: 0.927

Gnomad EAS exome AF: 0.701

Gnomad FIN exome AF: 0.969

Gnomad NFE exome AF: 0.960

Gnomad OTH exome AF: 0.889

GnomAD4 exome AF: 0.931 AC: 1298699 AN: 1395524 Hom.: 610409 Cov.: 50 AF XY: 0.931 AC XY: 640552 AN XY: 688178

African (AFR) AF: 0.454 AC: 14203 AN: 31302

American (AMR) AF: 0.766 AC: 26458 AN: 34554

Ashkenazi Jewish (ASJ) AF: 0.925 AC: 23247 AN: 25120

East Asian (EAS) AF: 0.724 AC: 25827 AN: 35656

South Asian (SAS) AF: 0.869 AC: 67895 AN: 78170

European-Finnish (FIN) AF: 0.968 AC: 47697 AN: 49254

Middle Eastern (MID) AF: 0.915 AC: 4916 AN: 5372

European-Non Finnish (NFE) AF: 0.961 AC: 1036730 AN: 1078258

Other (OTH) AF: 0.894 AC: 51726 AN: 57838

GnomAD4 genome AF: 0.798 AC: 121312 AN: 152086 Hom.: 51748 Cov.: 31 AF XY: 0.798 AC XY: 59301 AN XY: 74346

African (AFR) AF: 0.473 AC: 19596 AN: 41390

American (AMR) AF: 0.796 AC: 12168 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.916 AC: 3182 AN: 3472

East Asian (EAS) AF: 0.712 AC: 3671 AN: 5158

South Asian (SAS) AF: 0.852 AC: 4110 AN: 4824

European-Finnish (FIN) AF: 0.967 AC: 10257 AN: 10602

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.962 AC: 65442 AN: 68030

Other (OTH) AF: 0.823 AC: 1742 AN: 2116

Alfa AF: 0.921 Hom.: 17111

Bravo AF: 0.769

TwinsUK AF: 0.960 AC: 3560

ALSPAC AF: 0.955 AC: 3679

ESP6500AA AF: 0.519 AC: 718

ESP6500EA AF: 0.961 AC: 3053

ExAC AF: 0.860 AC: 19727

Asia WGS AF: 0.753 AC: 2618 AN: 3474

ClinVar

ClinVar submissions

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
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	11
DANN	Benign	0.067
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	5.7e-7	T
MetaSVM	Benign	-0.96	T
PhyloP100		0.36
PrimateAI	Benign	0.44	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.027
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.043
ClinPred		0.0035	T
GERP RS		2.4
Varity_R		0.044
Mutation Taster		=93/7	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: rs3105559; hg19: chr1-225266966; COSMIC: COSV107407496;