rs3856145

Positions:

• chr1-225340481-C-A
• chr1-225340481-C-G

Variant summary

Our verdict is Benign. Variant got -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. 12/16 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH14	NM_001367479.1	c.10458C>A	p.Asp3486Glu	missense_variant	69/86	ENST00000682510.1	NP_001354408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH14	ENST00000682510.1	c.10458C>A	p.Asp3486Glu	missense_variant	69/86		NM_001367479.1	ENSP00000508305.1

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

GnomAD3 exomes AF: 0.460 AC: 70773 AN: 153738 Hom.: 16692 AF XY: 0.462 AC XY: 37726 AN XY: 81582

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 SAS exome AF: 0.547

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

Gnomad4 AFR exome AF: 0.622

Gnomad4 AMR exome AF: 0.481

Gnomad4 ASJ exome AF: 0.343

Gnomad4 EAS exome AF: 0.481

Gnomad4 SAS exome AF: 0.544

Gnomad4 FIN exome AF: 0.369

Gnomad4 NFE exome AF: 0.431

Gnomad4 OTH exome AF: 0.441

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

Gnomad4 AFR AF: 0.618

Gnomad4 AMR AF: 0.464

Gnomad4 ASJ AF: 0.338

Gnomad4 EAS AF: 0.505

Gnomad4 SAS AF: 0.552

Gnomad4 FIN AF: 0.353

Gnomad4 NFE AF: 0.428

Gnomad4 OTH AF: 0.464

Alfa AF: 0.436 Hom.: 19411

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

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;T;.
MetaRNN	Benign	0.000043	T;T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.85	N;N;N
REVEL	Benign	0.019
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.34	.;B;B
Vest4		0.023
MutPred		0.31		.;Gain of disorder (P = 0.1585);Gain of disorder (P = 0.1585);
ClinPred		0.018	T
GERP RS		0.72
Varity_R		0.040

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

Publications

LitVar

Other links and lift over

dbSNP: rs3856145; hg19: chr1-225528183; COSMIC: COSV59896446;