1-224964520-C-T

Variant names:

• chr1-224964520-C-T
• rs192345324
• NM_001367479.1:c.409C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PVS1 BP6 BS2

The NM_001367479.1(DNAH14):​c.409C>T​(p.Arg137*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,609,766 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (6 hom.)
• Consequence: DNAH14 NM_001367479.1 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.632
• Publications: 7 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
• primary ciliary dyskinesia

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 1-224964520-C-T is Benign according to our data. Variant chr1-224964520-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2576886.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH14	NM_001367479.1	MANE Select	c.409C>T	p.Arg137*	stop_gained	Exon 5 of 86	NP_001354408.1	A0A804HLD3
	DNAH14	NM_001145154.3		c.409C>T	p.Arg137*	stop_gained	Exon 5 of 11	NP_001138626.1	Q0VDD8-2
	DNAH14	NM_001349911.2		c.409C>T	p.Arg137*	stop_gained	Exon 5 of 11	NP_001336840.1	M9MMK7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH14	ENST00000682510.1	MANE Select	c.409C>T	p.Arg137*	stop_gained	Exon 5 of 86	ENSP00000508305.1	A0A804HLD3
	DNAH14	ENST00000400952.7	TSL:1	c.409C>T	p.Arg137*	stop_gained	Exon 5 of 11	ENSP00000383737.3	Q0VDD8-2
	DNAH14	ENST00000366849.5	TSL:1	c.409C>T	p.Arg137*	stop_gained	Exon 5 of 11	ENSP00000355814.1	M9MMK7

Frequencies

GnomAD3 genomes AF: 0.000902 AC: 137 AN: 151934 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000695 AC: 173 AN: 248796 AF XY: 0.000711

Gnomad AFR exome AF: 0.000453

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00142

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.00176 AC: 2565 AN: 1457714 Hom.: 6 Cov.: 30 AF XY: 0.00168 AC XY: 1217 AN XY: 725156

African (AFR) AF: 0.000180 AC: 6 AN: 33392

American (AMR) AF: 0.000112 AC: 5 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39524

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85518

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00213 AC: 2366 AN: 1109542

Other (OTH) AF: 0.00308 AC: 185 AN: 60160

GnomAD4 genome AF: 0.000901 AC: 137 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.000874 AC XY: 65 AN XY: 74342

African (AFR) AF: 0.000434 AC: 18 AN: 41494

American (AMR) AF: 0.0000656 AC: 1 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00172 AC: 117 AN: 67970

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00137 Hom.: 2

Bravo AF: 0.000910

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00344 AC: 28

ExAC AF: 0.000671 AC: 81

Asia WGS AF: 0.000289 AC: 1 AN: 3468

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Benign	0.17
Eigen_PC	Benign	-0.021
FATHMM_MKL	Benign	0.50	N
PhyloP100		0.63
Vest4		0.28
GERP RS		2.8
Mutation Taster		=157/43	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.44		Position offset: -41

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs192345324; hg19: chr1-225152222; COSMIC: COSV64781052; COSMIC: COSV64781052;