1-224952757-G-T

Variant names:

• chr1-224952757-G-T
• rs61745064
• NM_001367479.1:c.55G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 4P and 9B. PVS1_Strong BP6 BS1 BS2

The NM_001367479.1(DNAH14):​c.55G>T​(p.Glu19*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,600,652 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.010 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (19 hom.)
• Consequence: DNAH14 NM_001367479.1 stop_gained
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.577
• Publications: 9 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_benign. The variant received -5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.996 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• BP6: Variant 1-224952757-G-T is Benign according to our data. Variant chr1-224952757-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3033978.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.01 (1522/152268) while in subpopulation AFR AF = 0.0346 (1437/41542). AF 95% confidence interval is 0.0331. There are 21 homozygotes in GnomAd4. There are 707 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 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.55G>T	p.Glu19*	stop_gained	Exon 2 of 86	NP_001354408.1	A0A804HLD3
	DNAH14	NM_001145154.3		c.55G>T	p.Glu19*	stop_gained	Exon 2 of 11	NP_001138626.1	Q0VDD8-2
	DNAH14	NM_001349911.2		c.55G>T	p.Glu19*	stop_gained	Exon 2 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.55G>T	p.Glu19*	stop_gained	Exon 2 of 86	ENSP00000508305.1	A0A804HLD3
	DNAH14	ENST00000400952.7	TSL:1	c.55G>T	p.Glu19*	stop_gained	Exon 2 of 11	ENSP00000383737.3	Q0VDD8-2
	DNAH14	ENST00000366849.5	TSL:1	c.55G>T	p.Glu19*	stop_gained	Exon 2 of 11	ENSP00000355814.1	M9MMK7

Frequencies

GnomAD3 genomes AF: 0.00999 AC: 1520 AN: 152150 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00228 AC: 527 AN: 231152 AF XY: 0.00166

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.000316

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000963

Gnomad OTH exome AF: 0.00140

GnomAD4 exome AF: 0.00102 AC: 1474 AN: 1448384 Hom.: 19 Cov.: 29 AF XY: 0.000906 AC XY: 652 AN XY: 719694

African (AFR) AF: 0.0342 AC: 1123 AN: 32812

American (AMR) AF: 0.00222 AC: 95 AN: 42784

Ashkenazi Jewish (ASJ) AF: 0.000350 AC: 9 AN: 25746

East Asian (EAS) AF: 0.00 AC: 0 AN: 39358

South Asian (SAS) AF: 0.0000239 AC: 2 AN: 83810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52830

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5722

European-Non Finnish (NFE) AF: 0.000103 AC: 114 AN: 1105558

Other (OTH) AF: 0.00204 AC: 122 AN: 59764

GnomAD4 genome AF: 0.0100 AC: 1522 AN: 152268 Hom.: 21 Cov.: 32 AF XY: 0.00949 AC XY: 707 AN XY: 74462

African (AFR) AF: 0.0346 AC: 1437 AN: 41542

American (AMR) AF: 0.00307 AC: 47 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68020

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.0184 Hom.: 2366

Bravo AF: 0.0112

ESP6500AA AF: 0.0344 AC: 124

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00273 AC: 330

Asia WGS AF: 0.00173 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	DNAH14-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Benign	0.066
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.039	N
PhyloP100		0.58
Vest4		0.15
GERP RS		-0.72
PromoterAI		-0.049	Neutral
Mutation Taster		=109/91	disease causing (fs/PTC)

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: rs61745064; hg19: chr1-225140459; COSMIC: COSV64782115; COSMIC: COSV64782115;