rs3856145

Variant names:

• chr1-225340481-C-A
• rs3856145
• NM_001367479.1:c.10458C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-225340481-C-A
• chr1-225340481-C-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.10458C>A​(p.Asp3486Glu) 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 1,548,676 control chromosomes in the GnomAD database, including 155,798 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18403 hom., cov: 32)
  • Exomes 𝑓: 0.44 (137395 hom.)
• Consequence: DNAH14 NM_001367479.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.346
• 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=4.2764386E-5).
• BP6: Variant 1-225340481-C-A is Benign according to our data. Variant chr1-225340481-C-A is described in ClinVar as Benign. ClinVar VariationId is 402656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.612 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.10458C>A	p.Asp3486Glu	missense	Exon 69 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.10458C>A	p.Asp3486Glu	missense	Exon 69 of 86	ENSP00000508305.1	A0A804HLD3
	DNAH14	ENST00000327794.10	TSL:1	n.3354C>A		non_coding_transcript_exon	Exon 25 of 40	ENSP00000328980.6	H7BXS7
	DNAH14	ENST00000430092.5	TSL:5	c.10179C>A	p.Asp3393Glu	missense	Exon 67 of 84	ENSP00000414402.1	Q0VDD8-4

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73382 AN: 151804 Hom.: 18372 Cov.: 32

Gnomad AFR AF: 0.618

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: 0.353

Gnomad MID AF: 0.395

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.462

GnomAD2 exomes AF: 0.460 AC: 70773 AN: 153738 AF XY: 0.462

Gnomad AFR exome AF: 0.630

Gnomad AMR exome AF: 0.487

Gnomad ASJ exome AF: 0.347

Gnomad EAS exome AF: 0.493

Gnomad FIN exome AF: 0.363

Gnomad NFE exome AF: 0.431

Gnomad OTH exome AF: 0.428

GnomAD4 exome AF: 0.441 AC: 615581 AN: 1396754 Hom.: 137395 Cov.: 35 AF XY: 0.444 AC XY: 305758 AN XY: 688872

African (AFR) AF: 0.622 AC: 19617 AN: 31538

American (AMR) AF: 0.481 AC: 17170 AN: 35680

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 8621 AN: 25140

East Asian (EAS) AF: 0.481 AC: 17139 AN: 35618

South Asian (SAS) AF: 0.544 AC: 43014 AN: 79068

European-Finnish (FIN) AF: 0.369 AC: 18147 AN: 49234

Middle Eastern (MID) AF: 0.413 AC: 2349 AN: 5688

European-Non Finnish (NFE) AF: 0.431 AC: 464015 AN: 1076884

Other (OTH) AF: 0.441 AC: 25509 AN: 57904

GnomAD4 genome AF: 0.484 AC: 73460 AN: 151922 Hom.: 18403 Cov.: 32 AF XY: 0.479 AC XY: 35565 AN XY: 74270

African (AFR) AF: 0.618 AC: 25610 AN: 41438

American (AMR) AF: 0.464 AC: 7075 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 1171 AN: 3468

East Asian (EAS) AF: 0.505 AC: 2606 AN: 5162

South Asian (SAS) AF: 0.552 AC: 2659 AN: 4814

European-Finnish (FIN) AF: 0.353 AC: 3713 AN: 10522

Middle Eastern (MID) AF: 0.384 AC: 112 AN: 292

European-Non Finnish (NFE) AF: 0.428 AC: 29081 AN: 67956

Other (OTH) AF: 0.464 AC: 977 AN: 2106

Alfa AF: 0.445 Hom.: 43620

Bravo AF: 0.499

TwinsUK AF: 0.435 AC: 1612

ALSPAC AF: 0.434 AC: 1671

ESP6500AA AF: 0.611 AC: 846

ESP6500EA AF: 0.441 AC: 1403

ExAC AF: 0.472 AC: 9998

Asia WGS AF: 0.538 AC: 1868 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.000043	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.35
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.019
Sift	Benign	0.28	T
Sift4G	Benign	0.18	T
Polyphen		0.34	B
Vest4		0.023
MutPred		0.31		Gain of disorder (P = 0.1585)
ClinPred		0.018	T
GERP RS		0.72
Varity_R		0.040
Mutation Taster		=95/5	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: rs3856145; hg19: chr1-225528183; COSMIC: COSV59896446;