rs12737248

Positions:

• chr1-225367900-T-G

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.12186T>G​(p.Asn4062Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.517 in 1,550,736 control chromosomes in the GnomAD database, including 215,967 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16912 hom., cov: 33)
  • Exomes 𝑓: 0.53 (199055 hom.)
• Consequence: DNAH14 NM_001367479.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.64

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=1.3750609E-5).
• BP6: Variant 1-225367900-T-G is Benign according to our data. Variant chr1-225367900-T-G is described in ClinVar as [Benign]. Clinvar id is 402662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH14	NM_001367479.1	c.12186T>G	p.Asn4062Lys	missense_variant	77/86	ENST00000682510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH14	ENST00000682510.1	c.12186T>G	p.Asn4062Lys	missense_variant	77/86		NM_001367479.1	P1

Frequencies

GnomAD3 genomes AF: 0.448 AC: 68157 AN: 152014 Hom.: 16910 Cov.: 33

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.526

Gnomad AMR AF: 0.465

Gnomad ASJ AF: 0.638

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.565

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.562

Gnomad OTH AF: 0.478

GnomAD3 exomes AF: 0.461 AC: 71005 AN: 154008 Hom.: 17786 AF XY: 0.460 AC XY: 37576 AN XY: 81738

Gnomad AFR exome AF: 0.250

Gnomad AMR exome AF: 0.390

Gnomad ASJ exome AF: 0.641

Gnomad EAS exome AF: 0.218

Gnomad SAS exome AF: 0.327

Gnomad FIN exome AF: 0.560

Gnomad NFE exome AF: 0.558

Gnomad OTH exome AF: 0.535

GnomAD4 exome AF: 0.525 AC: 734272 AN: 1398604 Hom.: 199055 Cov.: 42 AF XY: 0.521 AC XY: 359341 AN XY: 689818

Gnomad4 AFR exome AF: 0.242

Gnomad4 AMR exome AF: 0.401

Gnomad4 ASJ exome AF: 0.639

Gnomad4 EAS exome AF: 0.212

Gnomad4 SAS exome AF: 0.328

Gnomad4 FIN exome AF: 0.565

Gnomad4 NFE exome AF: 0.558

Gnomad4 OTH exome AF: 0.514

GnomAD4 genome AF: 0.448 AC: 68169 AN: 152132 Hom.: 16912 Cov.: 33 AF XY: 0.445 AC XY: 33060 AN XY: 74350

Gnomad4 AFR AF: 0.250

Gnomad4 AMR AF: 0.465

Gnomad4 ASJ AF: 0.638

Gnomad4 EAS AF: 0.218

Gnomad4 SAS AF: 0.302

Gnomad4 FIN AF: 0.565

Gnomad4 NFE AF: 0.562

Gnomad4 OTH AF: 0.476

Alfa AF: 0.540 Hom.: 55151

Bravo AF: 0.433

TwinsUK AF: 0.547 AC: 2027

ALSPAC AF: 0.557 AC: 2147

ESP6500AA AF: 0.259 AC: 358

ESP6500EA AF: 0.560 AC: 1781

ExAC AF: 0.425 AC: 8987

Asia WGS AF: 0.276 AC: 961 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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 -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.91	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.0070
DANN	Benign	0.68
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0056	N
LIST_S2	Benign	0.33	T;.
MetaRNN	Benign	0.000014	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.35	N;N
REVEL	Benign	0.034
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;B
Vest4		0.034
MutPred		0.59		Gain of ubiquitination at N3969 (P = 0.0162);Gain of ubiquitination at N3969 (P = 0.0162);
ClinPred		0.022	T
GERP RS		-10

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: rs12737248; hg19: chr1-225555602; COSMIC: COSV59895722;