rs12742757

Variant names:

• chr1-225346029-T-A
• rs12742757
• NM_001367479.1:c.10746T>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001367479.1(DNAH14):​c.10746T>A​(p.Ile3582Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0876 in 1,551,380 control chromosomes in the GnomAD database, including 7,724 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1173 hom., cov: 32)
  • Exomes 𝑓: 0.085 (6551 hom.)
• Consequence: DNAH14 NM_001367479.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.813
• Publications: 10 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 1-225346029-T-A is Benign according to our data. Variant chr1-225346029-T-A is described in ClinVar as [Benign]. Clinvar id is 402658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.813 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH14	NM_001367479.1	c.10746T>A	p.Ile3582Ile	synonymous_variant	Exon 70 of 86	ENST00000682510.1	NP_001354408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH14	ENST00000682510.1	c.10746T>A	p.Ile3582Ile	synonymous_variant	Exon 70 of 86		NM_001367479.1	ENSP00000508305.1

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17255 AN: 151948 Hom.: 1170 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.0502

Gnomad EAS AF: 0.258

Gnomad SAS AF: 0.0902

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0749

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.120 AC: 18615 AN: 155208 AF XY: 0.112

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.226

Gnomad ASJ exome AF: 0.0478

Gnomad EAS exome AF: 0.271

Gnomad FIN exome AF: 0.134

Gnomad NFE exome AF: 0.0709

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.0848 AC: 118628 AN: 1399316 Hom.: 6551 Cov.: 42 AF XY: 0.0841 AC XY: 58012 AN XY: 690176

African (AFR) AF: 0.149 AC: 4695 AN: 31592

American (AMR) AF: 0.216 AC: 7719 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.0485 AC: 1221 AN: 25178

East Asian (EAS) AF: 0.277 AC: 9883 AN: 35734

South Asian (SAS) AF: 0.0745 AC: 5902 AN: 79232

European-Finnish (FIN) AF: 0.135 AC: 6671 AN: 49258

Middle Eastern (MID) AF: 0.0479 AC: 273 AN: 5698

European-Non Finnish (NFE) AF: 0.0713 AC: 76877 AN: 1078936

Other (OTH) AF: 0.0929 AC: 5387 AN: 57994

GnomAD4 genome AF: 0.114 AC: 17275 AN: 152064 Hom.: 1173 Cov.: 32 AF XY: 0.119 AC XY: 8819 AN XY: 74346

African (AFR) AF: 0.144 AC: 5990 AN: 41470

American (AMR) AF: 0.164 AC: 2498 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0502 AC: 174 AN: 3466

East Asian (EAS) AF: 0.257 AC: 1328 AN: 5168

South Asian (SAS) AF: 0.0884 AC: 426 AN: 4820

European-Finnish (FIN) AF: 0.139 AC: 1472 AN: 10564

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0749 AC: 5095 AN: 67982

Other (OTH) AF: 0.103 AC: 219 AN: 2116

Alfa AF: 0.0832 Hom.: 213

Bravo AF: 0.118

Asia WGS AF: 0.170 AC: 591 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 11, 2022

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	6.2
DANN	Benign	0.68
PhyloP100		0.81
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: rs12742757; hg19: chr1-225533731; COSMIC: COSV59895710;