1-225085546-G-T

Variant names:

• chr1-225085546-G-T
• rs3128658
• NM_001367479.1:c.3330G>T

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.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. 14/17 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
• Publications: 20 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=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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367479.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH14	NM_001367479.1	MANE Select	c.3330G>T	p.Met1110Ile	missense splice_region	Exon 21 of 86	NP_001354408.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH14	ENST00000682510.1	MANE Select	c.3330G>T	p.Met1110Ile	missense splice_region	Exon 21 of 86	ENSP00000508305.1
	DNAH14	ENST00000430092.5	TSL:5	c.3330G>T	p.Met1110Ile	missense splice_region	Exon 21 of 84	ENSP00000414402.1
	DNAH14	ENST00000439375.6	TSL:5	c.3330G>T	p.Met1110Ile	missense splice_region	Exon 20 of 83	ENSP00000392061.2

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

GnomAD2 exomes AF: 0.869 AC: 134282 AN: 154508 AF XY: 0.879

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 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

African (AFR) AF: 0.453 AC: 14183 AN: 31292

American (AMR) AF: 0.766 AC: 27079 AN: 35352

Ashkenazi Jewish (ASJ) AF: 0.925 AC: 23133 AN: 24998

East Asian (EAS) AF: 0.724 AC: 25718 AN: 35530

South Asian (SAS) AF: 0.869 AC: 68290 AN: 78614

European-Finnish (FIN) AF: 0.968 AC: 47642 AN: 49198

Middle Eastern (MID) AF: 0.915 AC: 5177 AN: 5660

European-Non Finnish (NFE) AF: 0.962 AC: 1029441 AN: 1070610

Other (OTH) AF: 0.894 AC: 51506 AN: 57598

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

African (AFR) AF: 0.473 AC: 19638 AN: 41482

American (AMR) AF: 0.796 AC: 12179 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.916 AC: 3182 AN: 3472

East Asian (EAS) AF: 0.711 AC: 3672 AN: 5164

South Asian (SAS) AF: 0.852 AC: 4117 AN: 4830

European-Finnish (FIN) AF: 0.968 AC: 10268 AN: 10612

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.962 AC: 65436 AN: 68022

Other (OTH) AF: 0.823 AC: 1736 AN: 2110

Alfa AF: 0.917 Hom.: 268835

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
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
MetaSVM	Benign	-1.0	T
PhyloP100		1.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.071
Sift	Benign	0.56	T
Sift4G	Benign	0.34	T
Polyphen		0.11	B
Vest4		0.16
MutPred		0.50		Gain of methylation at K1109 (P = 0.0499)
ClinPred		0.010	T
GERP RS		3.9
Mutation Taster		=92/8	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: rs3128658; hg19: chr1-225273248; COSMIC: COSV107407497;