chr1-225085546-G-T

Position:

• chr1-225085546-G-T

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.3330G>T​(p.Met1110Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.917 in 1,541,050 control chromosomes in the GnomAD database, including 659,007 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (51766 hom., cov: 33)
  • Exomes 𝑓: 0.93 (607241 hom.)
• Consequence: DNAH14 NM_001367479.1 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.58

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=7.10634E-7).
• BP6: Variant 1-225085546-G-T is Benign according to our data. Variant chr1-225085546-G-T is described in ClinVar as [Benign]. Clinvar id is 402650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH14	NM_001367479.1	c.3330G>T	p.Met1110Ile	missense_variant, splice_region_variant	21/86	ENST00000682510.1	NP_001354408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH14	ENST00000682510.1	c.3330G>T	p.Met1110Ile	missense_variant, splice_region_variant	21/86		NM_001367479.1	ENSP00000508305	P1
DNAH14	ENST00000430092.5	c.3330G>T	p.Met1110Ile	missense_variant, splice_region_variant	21/84	5		ENSP00000414402
DNAH14	ENST00000439375.6	c.3330G>T	p.Met1110Ile	missense_variant, splice_region_variant	20/83	5		ENSP00000392061
DNAH14	ENST00000445597.6	c.2939-131G>T		intron_variant		5		ENSP00000409472

Frequencies

GnomAD3 genomes AF: 0.798 AC: 121318 AN: 152080 Hom.: 51748 Cov.: 33

Gnomad AFR AF: 0.474

Gnomad AMI AF: 0.980

Gnomad AMR AF: 0.796

Gnomad ASJ AF: 0.916

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.851

Gnomad FIN AF: 0.968

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.962

Gnomad OTH AF: 0.822

GnomAD3 exomes AF: 0.869 AC: 134282 AN: 154508 Hom.: 59709 AF XY: 0.879 AC XY: 71995 AN XY: 81946

Gnomad AFR exome AF: 0.471

Gnomad AMR exome AF: 0.760

Gnomad ASJ exome AF: 0.927

Gnomad EAS exome AF: 0.702

Gnomad SAS exome AF: 0.868

Gnomad FIN exome AF: 0.969

Gnomad NFE exome AF: 0.960

Gnomad OTH exome AF: 0.889

GnomAD4 exome AF: 0.930 AC: 1292169 AN: 1388852 Hom.: 607241 Cov.: 34 AF XY: 0.931 AC XY: 638042 AN XY: 685630

Gnomad4 AFR exome AF: 0.453

Gnomad4 AMR exome AF: 0.766

Gnomad4 ASJ exome AF: 0.925

Gnomad4 EAS exome AF: 0.724

Gnomad4 SAS exome AF: 0.869

Gnomad4 FIN exome AF: 0.968

Gnomad4 NFE exome AF: 0.962

Gnomad4 OTH exome AF: 0.894

GnomAD4 genome AF: 0.797 AC: 121372 AN: 152198 Hom.: 51766 Cov.: 33 AF XY: 0.797 AC XY: 59338 AN XY: 74420

Gnomad4 AFR AF: 0.473

Gnomad4 AMR AF: 0.796

Gnomad4 ASJ AF: 0.916

Gnomad4 EAS AF: 0.711

Gnomad4 SAS AF: 0.852

Gnomad4 FIN AF: 0.968

Gnomad4 NFE AF: 0.962

Gnomad4 OTH AF: 0.823

Alfa AF: 0.927 Hom.: 152571

Bravo AF: 0.769

TwinsUK AF: 0.960 AC: 3560

ALSPAC AF: 0.955 AC: 3679

ESP6500AA AF: 0.516 AC: 714

ESP6500EA AF: 0.960 AC: 3042

ExAC AF: 0.856 AC: 19704

Asia WGS AF: 0.754 AC: 2615 AN: 3468

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	-0.62	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Benign	0.55
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.45	T;.
MetaRNN	Benign	7.1e-7	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.61	N;N
REVEL	Benign	0.071
Sift	Benign	0.56	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.11	B;B
Vest4		0.16
MutPred		0.50		Gain of methylation at K1109 (P = 0.0499);Gain of methylation at K1109 (P = 0.0499);
ClinPred		0.010	T
GERP RS		3.9

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: rs3128658; hg19: chr1-225273248;