rs188496398

Positions:

• chr1-225152718-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001367479.1(DNAH14):​c.5031C>G​(p.Leu1677Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,549,856 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (40 hom.)
• Consequence: DNAH14 NM_001367479.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.289

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 1-225152718-C-G is Benign according to our data. Variant chr1-225152718-C-G is described in ClinVar as [Benign]. Clinvar id is 402651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.289 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00299 (4173/1397686) while in subpopulation MID AF= 0.0338 (192/5686). AF 95% confidence interval is 0.0299. There are 40 homozygotes in gnomad4_exome. There are 2351 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH14	NM_001367479.1	c.5031C>G	p.Leu1677Leu	synonymous_variant	33/86	ENST00000682510.1	NP_001354408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH14	ENST00000682510.1	c.5031C>G	p.Leu1677Leu	synonymous_variant	33/86		NM_001367479.1	ENSP00000508305.1
DNAH14	ENST00000430092.5	c.4980C>G	p.Leu1660Leu	synonymous_variant	32/84	5		ENSP00000414402.1
DNAH14	ENST00000439375.6	c.4980C>G	p.Leu1660Leu	synonymous_variant	31/83	5		ENSP00000392061.2
DNAH14	ENST00000445597.6	c.3750C>G	p.Leu1250Leu	synonymous_variant	20/61	5		ENSP00000409472.2

Frequencies

GnomAD3 genomes AF: 0.00316 AC: 480 AN: 152052 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.00361

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00268

Gnomad OTH AF: 0.00910

GnomAD3 exomes AF: 0.00589 AC: 915 AN: 155242 Hom.: 15 AF XY: 0.00656 AC XY: 540 AN XY: 82314

Gnomad AFR exome AF: 0.000636

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.0321

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0161

Gnomad FIN exome AF: 0.000298

Gnomad NFE exome AF: 0.00283

Gnomad OTH exome AF: 0.00827

GnomAD4 exome AF: 0.00299 AC: 4173 AN: 1397686 Hom.: 40 Cov.: 31 AF XY: 0.00341 AC XY: 2351 AN XY: 689192

Gnomad4 AFR exome AF: 0.000761

Gnomad4 AMR exome AF: 0.00259

Gnomad4 ASJ exome AF: 0.0295

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0151

Gnomad4 FIN exome AF: 0.000305

Gnomad4 NFE exome AF: 0.00147

Gnomad4 OTH exome AF: 0.00581

GnomAD4 genome AF: 0.00316 AC: 481 AN: 152170 Hom.: 5 Cov.: 32 AF XY: 0.00344 AC XY: 256 AN XY: 74390

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00360

Gnomad4 ASJ AF: 0.0297

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0127

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00268

Gnomad4 OTH AF: 0.00948

Alfa AF: 0.00603 Hom.: 2

Bravo AF: 0.00312

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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: Silent variant not in splice consensus -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.2
DANN	Benign	0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs188496398; hg19: chr1-225340420;