rs115366080

chr1-225080404-C-Achr1-225080404-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001367479.1(DNAH14):c.2792C>A(p.Ala931Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0373 in 1,545,784 control chromosomes in the GnomAD database, including 1,263 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.029 (84 hom., cov: 31)
  • Exomes 𝑓: 0.038 (1179 hom.)
• Consequence: DNAH14 NM_001367479.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.857

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018931329).
• BP6: Variant 1-225080404-C-A is Benign according to our data. Variant chr1-225080404-C-A is described in ClinVar as [Benign]. Clinvar id is 402646.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-225080404-C-A is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0629 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH14	NM_001367479.1	c.2792C>A	p.Ala931Asp	missense_variant	19/86	ENST00000682510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH14	ENST00000682510.1	c.2792C>A	p.Ala931Asp	missense_variant	19/86		NM_001367479.1	P1
DNAH14	ENST00000430092.5	c.2792C>A	p.Ala931Asp	missense_variant	19/84	5
DNAH14	ENST00000439375.6	c.2792C>A	p.Ala931Asp	missense_variant	18/83	5
DNAH14	ENST00000445597.6	c.2594C>A	p.Ala865Asp	missense_variant	15/61	5

Frequencies

GnomAD3 genomes AF: 0.0292 AC: 4442 AN: 152172 Hom.: 84 Cov.: 31

Gnomad AFR AF: 0.00688

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0187

Gnomad ASJ AF: 0.0622

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0311

Gnomad FIN AF: 0.0580

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0397

Gnomad OTH AF: 0.0311

GnomAD3 exomes AF: 0.0348 AC: 5274 AN: 151610 Hom.: 134 AF XY: 0.0358 AC XY: 2860 AN XY: 79908

Gnomad AFR exome AF: 0.00624

Gnomad AMR exome AF: 0.0177

Gnomad ASJ exome AF: 0.0615

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0360

Gnomad FIN exome AF: 0.0630

Gnomad NFE exome AF: 0.0398

Gnomad OTH exome AF: 0.0383

GnomAD4 exome AF: 0.0382 AC: 53162 AN: 1393494 Hom.: 1179 Cov.: 30 AF XY: 0.0383 AC XY: 26302 AN XY: 686850

Gnomad4 AFR exome AF: 0.00597

Gnomad4 AMR exome AF: 0.0190

Gnomad4 ASJ exome AF: 0.0616

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0362

Gnomad4 FIN exome AF: 0.0582

Gnomad4 NFE exome AF: 0.0395

Gnomad4 OTH exome AF: 0.0376

GnomAD4 genome AF: 0.0292 AC: 4443 AN: 152290 Hom.: 84 Cov.: 31 AF XY: 0.0299 AC XY: 2228 AN XY: 74450

Gnomad4 AFR AF: 0.00686

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.0622

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0313

Gnomad4 FIN AF: 0.0580

Gnomad4 NFE AF: 0.0397

Gnomad4 OTH AF: 0.0312

Alfa AF: 0.0361 Hom.: 156

Bravo AF: 0.0260

TwinsUK AF: 0.0450 AC: 167

ALSPAC AF: 0.0392 AC: 151

ESP6500AA AF: 0.00795 AC: 11

ESP6500EA AF: 0.0402 AC: 128

ExAC AF: 0.0367 AC: 918

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	0.29
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	6.0
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0096	T;.;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.31	T;T;.
MetaRNN	Benign	0.0019	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Benign	0.038
Sift	Uncertain	0.014	D;T;T
Sift4G	Uncertain	0.042	D;T;T
Polyphen		0.22	.;B;B
Vest4		0.29
ClinPred		0.0031	T
GERP RS		-1.3
Varity_R		0.18

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: rs115366080; hg19: chr1-225268106; COSMIC: COSV100144847;