NM_001367479.1:c.11288G>A

Variant names:

• chr1-225346646-G-A
• rs7535953
• NM_001367479.1:c.11288G>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.11288G>A​(p.Arg3763Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 1,539,904 control chromosomes in the GnomAD database, including 154,539 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18352 hom., cov: 31)
  • Exomes 𝑓: 0.44 (136187 hom.)
• Consequence: DNAH14 NM_001367479.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.104
• Publications: 14 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=1.3200319E-5).
• BP6: Variant 1-225346646-G-A is Benign according to our data. Variant chr1-225346646-G-A is described in ClinVar as Benign. ClinVar VariationId is 402660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.609 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.11288G>A	p.Arg3763Lys	missense	Exon 71 of 86	NP_001354408.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH14	ENST00000682510.1	MANE Select	c.11288G>A	p.Arg3763Lys	missense	Exon 71 of 86	ENSP00000508305.1
	DNAH14	ENST00000327794.10	TSL:1	n.4184G>A		non_coding_transcript_exon	Exon 27 of 40	ENSP00000328980.6
	DNAH14	ENST00000430092.5	TSL:5	c.11009G>A	p.Arg3670Lys	missense	Exon 69 of 84	ENSP00000414402.1

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73297 AN: 151754 Hom.: 18321 Cov.: 31

Gnomad AFR AF: 0.616

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.507

Gnomad SAS AF: 0.553

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.461

GnomAD2 exomes AF: 0.463 AC: 69057 AN: 149002 AF XY: 0.465

Gnomad AFR exome AF: 0.627

Gnomad AMR exome AF: 0.494

Gnomad ASJ exome AF: 0.350

Gnomad EAS exome AF: 0.496

Gnomad FIN exome AF: 0.365

Gnomad NFE exome AF: 0.434

Gnomad OTH exome AF: 0.432

GnomAD4 exome AF: 0.440 AC: 611174 AN: 1388032 Hom.: 136187 Cov.: 32 AF XY: 0.444 AC XY: 303773 AN XY: 684808

African (AFR) AF: 0.619 AC: 19161 AN: 30954

American (AMR) AF: 0.485 AC: 16783 AN: 34578

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 8544 AN: 24864

East Asian (EAS) AF: 0.481 AC: 17122 AN: 35578

South Asian (SAS) AF: 0.544 AC: 42608 AN: 78298

European-Finnish (FIN) AF: 0.369 AC: 18112 AN: 49116

Middle Eastern (MID) AF: 0.417 AC: 1987 AN: 4766

European-Non Finnish (NFE) AF: 0.430 AC: 461578 AN: 1072414

Other (OTH) AF: 0.440 AC: 25279 AN: 57464

GnomAD4 genome AF: 0.483 AC: 73375 AN: 151872 Hom.: 18352 Cov.: 31 AF XY: 0.478 AC XY: 35508 AN XY: 74230

African (AFR) AF: 0.616 AC: 25507 AN: 41430

American (AMR) AF: 0.464 AC: 7074 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 1171 AN: 3460

East Asian (EAS) AF: 0.506 AC: 2612 AN: 5164

South Asian (SAS) AF: 0.553 AC: 2662 AN: 4812

European-Finnish (FIN) AF: 0.354 AC: 3727 AN: 10520

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.428 AC: 29073 AN: 67922

Other (OTH) AF: 0.464 AC: 980 AN: 2114

Alfa AF: 0.447 Hom.: 45762

Bravo AF: 0.498

TwinsUK AF: 0.434 AC: 1608

ALSPAC AF: 0.434 AC: 1671

ExAC AF: 0.473 AC: 9945

Asia WGS AF: 0.539 AC: 1871 AN: 3476

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	0.095
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.83
DANN	Benign	0.66
DEOGEN2	Benign	0.0046	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0040	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.000013	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.10
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.022
Sift	Benign	0.087	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.013
ClinPred		0.0058	T
GERP RS		-3.8
Varity_R		0.046
Mutation Taster		=100/0	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: rs7535953; hg19: chr1-225534348; COSMIC: COSV59893614;