1-225082707-A-T

Variant names:

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

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.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. 11/16 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
• Publications: 25 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

ACMG classification

Our verdict: Benign. The variant received -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

GnomAD2 exomes AF: 0.811 AC: 126229 AN: 155660 AF XY: 0.818

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 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

African (AFR) AF: 0.425 AC: 13412 AN: 31524

American (AMR) AF: 0.737 AC: 26080 AN: 35406

Ashkenazi Jewish (ASJ) AF: 0.886 AC: 22277 AN: 25154

East Asian (EAS) AF: 0.723 AC: 25794 AN: 35688

South Asian (SAS) AF: 0.802 AC: 63459 AN: 79090

European-Finnish (FIN) AF: 0.875 AC: 43129 AN: 49264

Middle Eastern (MID) AF: 0.874 AC: 4967 AN: 5682

European-Non Finnish (NFE) AF: 0.884 AC: 953445 AN: 1078532

Other (OTH) AF: 0.831 AC: 48151 AN: 57946

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

African (AFR) AF: 0.438 AC: 18158 AN: 41438

American (AMR) AF: 0.761 AC: 11631 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.881 AC: 3052 AN: 3466

East Asian (EAS) AF: 0.702 AC: 3622 AN: 5156

South Asian (SAS) AF: 0.787 AC: 3799 AN: 4828

European-Finnish (FIN) AF: 0.874 AC: 9250 AN: 10578

Middle Eastern (MID) AF: 0.810 AC: 238 AN: 294

European-Non Finnish (NFE) AF: 0.884 AC: 60136 AN: 67994

Other (OTH) AF: 0.763 AC: 1609 AN: 2110

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
PhyloP100		1.6
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3128655; hg19: chr1-225270409; COSMIC: COSV60741408;