rs750506412

Variant names:

• chr1-224964478-G-A
• rs750506412
• NM_001367479.1:c.368-1G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001367479.1(DNAH14):​c.368-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00012 in 1,606,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: DNAH14 NM_001367479.1 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.3, offset of -50, new splice context is: tattatgcattatccttaAGtga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

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.368-1G>A		splice_acceptor intron	N/A	NP_001354408.1	A0A804HLD3
	DNAH14	NM_001145154.3		c.368-1G>A		splice_acceptor intron	N/A	NP_001138626.1	Q0VDD8-2
	DNAH14	NM_001349911.2		c.368-1G>A		splice_acceptor intron	N/A	NP_001336840.1	M9MMK7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH14	ENST00000682510.1	MANE Select	c.368-1G>A		splice_acceptor intron	N/A	ENSP00000508305.1	A0A804HLD3
	DNAH14	ENST00000400952.7	TSL:1	c.368-1G>A		splice_acceptor intron	N/A	ENSP00000383737.3	Q0VDD8-2
	DNAH14	ENST00000366849.5	TSL:1	c.368-1G>A		splice_acceptor intron	N/A	ENSP00000355814.1	M9MMK7

Frequencies

GnomAD3 genomes AF: 0.0000856 AC: 13 AN: 151866 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000109 AC: 27 AN: 247620 AF XY: 0.0000819

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.000176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000169

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000123 AC: 179 AN: 1454812 Hom.: 0 Cov.: 30 AF XY: 0.000116 AC XY: 84 AN XY: 723508

African (AFR) AF: 0.0000600 AC: 2 AN: 33340

American (AMR) AF: 0.000225 AC: 10 AN: 44352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25932

East Asian (EAS) AF: 0.00 AC: 0 AN: 39442

South Asian (SAS) AF: 0.00 AC: 0 AN: 84712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53108

Middle Eastern (MID) AF: 0.000699 AC: 4 AN: 5726

European-Non Finnish (NFE) AF: 0.000134 AC: 148 AN: 1108186

Other (OTH) AF: 0.000250 AC: 15 AN: 60014

GnomAD4 genome AF: 0.0000856 AC: 13 AN: 151866 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74142

African (AFR) AF: 0.0000725 AC: 3 AN: 41358

American (AMR) AF: 0.00 AC: 0 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67966

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.0000994 AC: 12

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		5.8
GERP RS		5.2
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.93		Position offset: 1

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

Other links and lift over

dbSNP: rs750506412; hg19: chr1-225152180;