chr1-225080404-C-A

Variant names:

• chr1-225080404-C-A
• rs115366080
• NM_001367479.1:c.2792C>A

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.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. 12/18 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.857
• Publications: 7 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=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 VariationId is 402646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
DNAH14	NM_001367479.1	c.2792C>A	p.Ala931Asp	missense_variant	Exon 19 of 86	ENST00000682510.1	NP_001354408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH14	ENST00000682510.1	c.2792C>A	p.Ala931Asp	missense_variant	Exon 19 of 86		NM_001367479.1	ENSP00000508305.1
DNAH14	ENST00000430092.5	c.2792C>A	p.Ala931Asp	missense_variant	Exon 19 of 84	5		ENSP00000414402.1
DNAH14	ENST00000439375.6	c.2792C>A	p.Ala931Asp	missense_variant	Exon 18 of 83	5		ENSP00000392061.2
DNAH14	ENST00000445597.6	c.2594C>A	p.Ala865Asp	missense_variant	Exon 15 of 61	5		ENSP00000409472.2

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

GnomAD2 exomes AF: 0.0348 AC: 5274 AN: 151610 AF XY: 0.0358

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 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

African (AFR) AF: 0.00597 AC: 188 AN: 31476

American (AMR) AF: 0.0190 AC: 667 AN: 35108

Ashkenazi Jewish (ASJ) AF: 0.0616 AC: 1522 AN: 24702

East Asian (EAS) AF: 0.00 AC: 0 AN: 35692

South Asian (SAS) AF: 0.0362 AC: 2822 AN: 77950

European-Finnish (FIN) AF: 0.0582 AC: 2858 AN: 49078

Middle Eastern (MID) AF: 0.0685 AC: 388 AN: 5664

European-Non Finnish (NFE) AF: 0.0395 AC: 42547 AN: 1076062

Other (OTH) AF: 0.0376 AC: 2170 AN: 57762

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

African (AFR) AF: 0.00686 AC: 285 AN: 41572

American (AMR) AF: 0.0186 AC: 285 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0622 AC: 216 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0313 AC: 151 AN: 4818

European-Finnish (FIN) AF: 0.0580 AC: 615 AN: 10610

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0397 AC: 2703 AN: 68016

Other (OTH) AF: 0.0312 AC: 66 AN: 2114

Alfa AF: 0.0355 Hom.: 342

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: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	0.29
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
PhyloP100		-0.86
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
Mutation Taster		=99/1	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: rs115366080; hg19: chr1-225268106;