1-225082707-A-T

Variant names:

• chr1-225082707-A-T
• rs3128655
• NM_001367479.1:c.3295A>T

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.3295A>T​(p.Asn1099Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.847 in 1,550,332 control chromosomes in the GnomAD database, including 564,641 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (44382 hom., cov: 32)
  • Exomes 𝑓: 0.86 (520259 hom.)
• Consequence: DNAH14 NM_001367479.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.59

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=1.0601531E-6).
• BP6: Variant 1-225082707-A-T is Benign according to our data. Variant chr1-225082707-A-T is described in ClinVar as [Benign]. Clinvar id is 402649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH14	NM_001367479.1	c.3295A>T	p.Asn1099Tyr	missense_variant	Exon 20 of 86	ENST00000682510.1	NP_001354408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH14	ENST00000682510.1	c.3295A>T	p.Asn1099Tyr	missense_variant	Exon 20 of 86		NM_001367479.1	ENSP00000508305.1
DNAH14	ENST00000430092.5	c.3295A>T	p.Asn1099Tyr	missense_variant	Exon 20 of 84	5		ENSP00000414402.1
DNAH14	ENST00000439375.6	c.3295A>T	p.Asn1099Tyr	missense_variant	Exon 19 of 83	5		ENSP00000392061.2
DNAH14	ENST00000445597.6	c.2938+1959A>T		intron_variant	Intron 15 of 60	5		ENSP00000409472.2

Frequencies

GnomAD3 genomes AF: 0.739 AC: 112308 AN: 151930 Hom.: 44375 Cov.: 32

Gnomad AFR AF: 0.438

Gnomad AMI AF: 0.936

Gnomad AMR AF: 0.762

Gnomad ASJ AF: 0.881

Gnomad EAS AF: 0.702

Gnomad SAS AF: 0.786

Gnomad FIN AF: 0.874

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.884

Gnomad OTH AF: 0.765

GnomAD3 exomes AF: 0.811 AC: 126229 AN: 155660 Hom.: 52247 AF XY: 0.818 AC XY: 67521 AN XY: 82502

Gnomad AFR exome AF: 0.439

Gnomad AMR exome AF: 0.732

Gnomad ASJ exome AF: 0.890

Gnomad EAS exome AF: 0.689

Gnomad SAS exome AF: 0.803

Gnomad FIN exome AF: 0.878

Gnomad NFE exome AF: 0.885

Gnomad OTH exome AF: 0.834

GnomAD4 exome AF: 0.859 AC: 1200714 AN: 1398286 Hom.: 520259 Cov.: 49 AF XY: 0.859 AC XY: 592624 AN XY: 689664

Gnomad4 AFR exome AF: 0.425

Gnomad4 AMR exome AF: 0.737

Gnomad4 ASJ exome AF: 0.886

Gnomad4 EAS exome AF: 0.723

Gnomad4 SAS exome AF: 0.802

Gnomad4 FIN exome AF: 0.875

Gnomad4 NFE exome AF: 0.884

Gnomad4 OTH exome AF: 0.831

GnomAD4 genome AF: 0.739 AC: 112345 AN: 152046 Hom.: 44382 Cov.: 32 AF XY: 0.739 AC XY: 54938 AN XY: 74334

Gnomad4 AFR AF: 0.438

Gnomad4 AMR AF: 0.761

Gnomad4 ASJ AF: 0.881

Gnomad4 EAS AF: 0.702

Gnomad4 SAS AF: 0.787

Gnomad4 FIN AF: 0.874

Gnomad4 NFE AF: 0.884

Gnomad4 OTH AF: 0.763

Alfa AF: 0.861 Hom.: 39130

Bravo AF: 0.717

TwinsUK AF: 0.877 AC: 3253

ALSPAC AF: 0.886 AC: 3415

ESP6500AA AF: 0.469 AC: 649

ESP6500EA AF: 0.889 AC: 2829

ExAC AF: 0.794 AC: 18560

Asia WGS AF: 0.713 AC: 2480 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.33	T;.
MetaRNN	Benign	0.0000011	T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Benign	0.23
Sift	Benign	0.25	T;T
Sift4G	Uncertain	0.019	D;D
Polyphen		0.96	D;D
Vest4		0.40
ClinPred		0.029	T
GERP RS		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs3128655; hg19: chr1-225270409; COSMIC: COSV60741408;