chr1-224967584-G-A

Variant names:

• chr1-224967584-G-A
• rs146938681
• NM_001367479.1:c.651+1G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PVS1_Moderate PP3 BP6 BS1 BS2

The NM_001367479.1(DNAH14):​c.651+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00199 in 1,599,268 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (27 hom.)
• Consequence: DNAH14 NM_001367479.1 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.45

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 Likely_benign. Variant got -6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.011043742 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP3: Multiple lines of computational evidence support a deleterious effect 5: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen [when BayesDel_addAF, MutationTaster was below the threshold]
• BP6: Variant 1-224967584-G-A is Benign according to our data. Variant chr1-224967584-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3056432.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00254 (386/151966) while in subpopulation EAS AF= 0.0219 (113/5156). AF 95% confidence interval is 0.0186. There are 4 homozygotes in gnomad4. There are 195 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH14	NM_001367479.1	c.651+1G>A		splice_donor_variant, intron_variant	Intron 6 of 85	ENST00000682510.1	NP_001354408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH14	ENST00000682510.1	c.651+1G>A		splice_donor_variant, intron_variant	Intron 6 of 85		NM_001367479.1	ENSP00000508305.1

Frequencies

GnomAD3 genomes AF: 0.00253 AC: 384 AN: 151848 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000701

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0219

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00576 AC: 1354 AN: 235122 Hom.: 20 AF XY: 0.00441 AC XY: 562 AN XY: 127492

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.0283

Gnomad ASJ exome AF: 0.00200

Gnomad EAS exome AF: 0.0220

Gnomad SAS exome AF: 0.000150

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000476

Gnomad OTH exome AF: 0.00300

GnomAD4 exome AF: 0.00193 AC: 2800 AN: 1447302 Hom.: 27 Cov.: 32 AF XY: 0.00167 AC XY: 1204 AN XY: 719516

Gnomad4 AFR exome AF: 0.000523

Gnomad4 AMR exome AF: 0.0260

Gnomad4 ASJ exome AF: 0.00148

Gnomad4 EAS exome AF: 0.0239

Gnomad4 SAS exome AF: 0.0000970

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000566

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00254 AC: 386 AN: 151966 Hom.: 4 Cov.: 32 AF XY: 0.00263 AC XY: 195 AN XY: 74270

Gnomad4 AFR AF: 0.000699

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0219

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00164 Hom.: 2

Bravo AF: 0.00370

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00111 AC: 4

ESP6500EA AF: 0.00111 AC: 9

ExAC AF: 0.00514 AC: 621

Asia WGS AF: 0.00723 AC: 25 AN: 3472

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

DNAH14-related disorder Benign:1

May 01, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	29
DANN	Uncertain	0.98
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.94	D
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs146938681; hg19: chr1-225155286;