rs3856154

chr1-225377313-T-Cchr1-225377313-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001367479.1(DNAH14):c.12593T>C(p.Leu4198Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 1,548,846 control chromosomes in the GnomAD database, including 317,763 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.58 (27332 hom., cov: 32)
  • Exomes 𝑓: 0.64 (290431 hom.)
• Consequence: DNAH14 NM_001367479.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.80

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.33696E-6).
• BP6: Variant 1-225377313-T-C is Benign according to our data. Variant chr1-225377313-T-C is described in ClinVar as [Benign]. Clinvar id is 402664.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH14	NM_001367479.1	c.12593T>C	p.Leu4198Pro	missense_variant	79/86	ENST00000682510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH14	ENST00000682510.1	c.12593T>C	p.Leu4198Pro	missense_variant	79/86		NM_001367479.1	P1

Frequencies

GnomAD3 genomes AF: 0.581 AC: 88326 AN: 151904 Hom.: 27315 Cov.: 32

Gnomad AFR AF: 0.356

Gnomad AMI AF: 0.550

Gnomad AMR AF: 0.726

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.764

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.694

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.656

Gnomad OTH AF: 0.623

GnomAD3 exomes AF: 0.638 AC: 97070 AN: 152100 Hom.: 32155 AF XY: 0.626 AC XY: 50507 AN XY: 80730

Gnomad AFR exome AF: 0.346

Gnomad AMR exome AF: 0.746

Gnomad ASJ exome AF: 0.703

Gnomad EAS exome AF: 0.759

Gnomad SAS exome AF: 0.466

Gnomad FIN exome AF: 0.689

Gnomad NFE exome AF: 0.651

Gnomad OTH exome AF: 0.682

GnomAD4 exome AF: 0.640 AC: 894053 AN: 1396824 Hom.: 290431 Cov.: 46 AF XY: 0.635 AC XY: 437648 AN XY: 688832

Gnomad4 AFR exome AF: 0.331

Gnomad4 AMR exome AF: 0.745

Gnomad4 ASJ exome AF: 0.705

Gnomad4 EAS exome AF: 0.780

Gnomad4 SAS exome AF: 0.469

Gnomad4 FIN exome AF: 0.690

Gnomad4 NFE exome AF: 0.649

Gnomad4 OTH exome AF: 0.640

GnomAD4 genome AF: 0.581 AC: 88371 AN: 152022 Hom.: 27332 Cov.: 32 AF XY: 0.585 AC XY: 43442 AN XY: 74322

Gnomad4 AFR AF: 0.355

Gnomad4 AMR AF: 0.726

Gnomad4 ASJ AF: 0.706

Gnomad4 EAS AF: 0.765

Gnomad4 SAS AF: 0.461

Gnomad4 FIN AF: 0.694

Gnomad4 NFE AF: 0.656

Gnomad4 OTH AF: 0.629

Alfa AF: 0.651 Hom.: 75378

Bravo AF: 0.580

TwinsUK AF: 0.643 AC: 2385

ALSPAC AF: 0.656 AC: 2529

ESP6500AA AF: 0.342 AC: 474

ESP6500EA AF: 0.657 AC: 2091

ExAC AF: 0.542 AC: 11668

Asia WGS AF: 0.590 AC: 2052 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.040
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
Cadd	Benign	14
Dann	Benign	0.90
DEOGEN2	Benign	0.00080	T;.;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.00024	N
LIST_S2	Benign	0.13	T;T;.
MetaRNN	Benign	0.0000013	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.5	N;N;N
REVEL	Benign	0.061
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.041
ClinPred		0.0032	T
GERP RS		4.3
Varity_R		0.071

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: rs3856154; hg19: chr1-225565015;