1-225345982-A-G

Variant names:

• chr1-225345982-A-G
• rs6667999
• NM_001367479.1:c.10699A>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.10699A>G​(p.Lys3567Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 1,548,984 control chromosomes in the GnomAD database, including 155,635 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18359 hom., cov: 32)
  • Exomes 𝑓: 0.44 (137276 hom.)
• Consequence: DNAH14 NM_001367479.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.23
• Publications: 21 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=1.5726708E-5).
• BP6: Variant 1-225345982-A-G is Benign according to our data. Variant chr1-225345982-A-G is described in ClinVar as Benign. ClinVar VariationId is 402657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.609 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.10699A>G	p.Lys3567Glu	missense	Exon 70 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.10699A>G	p.Lys3567Glu	missense	Exon 70 of 86	ENSP00000508305.1	A0A804HLD3
	DNAH14	ENST00000327794.10	TSL:1	n.3595A>G		non_coding_transcript_exon	Exon 26 of 40	ENSP00000328980.6	H7BXS7
	DNAH14	ENST00000430092.5	TSL:5	c.10420A>G	p.Lys3474Glu	missense	Exon 68 of 84	ENSP00000414402.1	Q0VDD8-4

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73321 AN: 151914 Hom.: 18328 Cov.: 32

Gnomad AFR AF: 0.615

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.506

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.461

GnomAD2 exomes AF: 0.460 AC: 70904 AN: 154222 AF XY: 0.462

Gnomad AFR exome AF: 0.627

Gnomad AMR exome AF: 0.488

Gnomad ASJ exome AF: 0.346

Gnomad EAS exome AF: 0.494

Gnomad FIN exome AF: 0.364

Gnomad NFE exome AF: 0.431

Gnomad OTH exome AF: 0.429

GnomAD4 exome AF: 0.441 AC: 615626 AN: 1396952 Hom.: 137276 Cov.: 37 AF XY: 0.444 AC XY: 305882 AN XY: 689126

African (AFR) AF: 0.620 AC: 19433 AN: 31344

American (AMR) AF: 0.481 AC: 16938 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 8592 AN: 25066

East Asian (EAS) AF: 0.481 AC: 17190 AN: 35726

South Asian (SAS) AF: 0.544 AC: 43046 AN: 79110

European-Finnish (FIN) AF: 0.369 AC: 18147 AN: 49232

Middle Eastern (MID) AF: 0.413 AC: 2353 AN: 5694

European-Non Finnish (NFE) AF: 0.431 AC: 464437 AN: 1077730

Other (OTH) AF: 0.441 AC: 25490 AN: 57850

GnomAD4 genome AF: 0.483 AC: 73399 AN: 152032 Hom.: 18359 Cov.: 32 AF XY: 0.478 AC XY: 35513 AN XY: 74322

African (AFR) AF: 0.615 AC: 25506 AN: 41466

American (AMR) AF: 0.464 AC: 7082 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 1173 AN: 3468

East Asian (EAS) AF: 0.505 AC: 2610 AN: 5170

South Asian (SAS) AF: 0.552 AC: 2661 AN: 4818

European-Finnish (FIN) AF: 0.352 AC: 3726 AN: 10578

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.428 AC: 29091 AN: 67952

Other (OTH) AF: 0.464 AC: 981 AN: 2116

Alfa AF: 0.446 Hom.: 53657

Bravo AF: 0.498

TwinsUK AF: 0.435 AC: 1612

ALSPAC AF: 0.434 AC: 1674

ESP6500AA AF: 0.608 AC: 842

ESP6500EA AF: 0.442 AC: 1406

ExAC AF: 0.465 AC: 10706

Asia WGS AF: 0.540 AC: 1875 AN: 3478

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	0.059
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	11
DANN	Benign	0.13
DEOGEN2	Benign	0.0021	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.0042	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.000016	T
MetaSVM	Benign	-0.92	T
PhyloP100		2.2
PrimateAI	Benign	0.44	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.071
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.031
ClinPred		0.0013	T
GERP RS		3.4
Varity_R		0.054
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: rs6667999; hg19: chr1-225533684; COSMIC: COSV100586725;