NM_001367479.1:c.11159T>C

Variant names:

• chr1-225346517-T-C
• rs7527925
• NM_001367479.1:c.11159T>C

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.11159T>C​(p.Val3720Ala) 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 1,550,514 control chromosomes in the GnomAD database, including 155,798 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18351 hom., cov: 32)
  • Exomes 𝑓: 0.44 (137447 hom.)
• Consequence: DNAH14 NM_001367479.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0710
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0780426E-5).
• BP6: Variant 1-225346517-T-C is Benign according to our data. Variant chr1-225346517-T-C is described in ClinVar as Benign. ClinVar VariationId is 402659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH14	NM_001367479.1	c.11159T>C	p.Val3720Ala	missense_variant	Exon 71 of 86	ENST00000682510.1	NP_001354408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH14	ENST00000682510.1	c.11159T>C	p.Val3720Ala	missense_variant	Exon 71 of 86		NM_001367479.1	ENSP00000508305.1

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73287 AN: 151852 Hom.: 18320 Cov.: 32

Gnomad AFR AF: 0.615

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.507

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.395

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.461

GnomAD2 exomes AF: 0.460 AC: 70697 AN: 153598 AF XY: 0.463

Gnomad AFR exome AF: 0.627

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: 616401 AN: 1398544 Hom.: 137447 Cov.: 42 AF XY: 0.444 AC XY: 306202 AN XY: 689822

African (AFR) AF: 0.620 AC: 19557 AN: 31560

American (AMR) AF: 0.481 AC: 17136 AN: 35636

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 8629 AN: 25162

East Asian (EAS) AF: 0.481 AC: 17177 AN: 35682

South Asian (SAS) AF: 0.544 AC: 43081 AN: 79178

European-Finnish (FIN) AF: 0.369 AC: 18156 AN: 49260

Middle Eastern (MID) AF: 0.414 AC: 2353 AN: 5690

European-Non Finnish (NFE) AF: 0.431 AC: 464767 AN: 1078404

Other (OTH) AF: 0.441 AC: 25545 AN: 57972

GnomAD4 genome AF: 0.483 AC: 73365 AN: 151970 Hom.: 18351 Cov.: 32 AF XY: 0.478 AC XY: 35498 AN XY: 74282

African (AFR) AF: 0.615 AC: 25492 AN: 41442

American (AMR) AF: 0.464 AC: 7082 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 1174 AN: 3472

East Asian (EAS) AF: 0.506 AC: 2610 AN: 5158

South Asian (SAS) AF: 0.552 AC: 2661 AN: 4818

European-Finnish (FIN) AF: 0.352 AC: 3713 AN: 10540

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

European-Non Finnish (NFE) AF: 0.428 AC: 29089 AN: 67956

Other (OTH) AF: 0.464 AC: 978 AN: 2110

Alfa AF: 0.445 Hom.: 75668

Bravo AF: 0.498

TwinsUK AF: 0.435 AC: 1613

ALSPAC AF: 0.435 AC: 1675

ESP6500AA AF: 0.608 AC: 842

ESP6500EA AF: 0.442 AC: 1404

ExAC AF: 0.476 AC: 10017

Asia WGS AF: 0.539 AC: 1868 AN: 3468

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
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Benign	0.59
DEOGEN2	Benign	0.0020	T;.;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.086	T;T;.
MetaRNN	Benign	0.000011	T;T;T
MetaSVM	Benign	-0.93	T
PhyloP100		0.071
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.54	N;N;N
REVEL	Benign	0.045
Sift	Benign	0.75	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.057
ClinPred		0.00093	T
GERP RS		3.5
Varity_R		0.026
Mutation Taster		=100/0	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: rs7527925; hg19: chr1-225534219; COSMIC: COSV100586726;