rs188496398

Variant names:

• chr1-225152718-C-G
• rs188496398
• NM_001367479.1:c.5031C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 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=-0.46).
• 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. GnomAdExome4 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 GnomAdExome4. There are 2351 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH14	NM_001367479.1	c.5031C>G	p.Leu1677Leu	synonymous_variant	Exon 33 of 86	ENST00000682510.1	NP_001354408.1

Ensembl

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

GnomAD2 exomes AF: 0.00589 AC: 915 AN: 155242 AF XY: 0.00656

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 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

African (AFR) AF: 0.000761 AC: 24 AN: 31518

American (AMR) AF: 0.00259 AC: 92 AN: 35492

Ashkenazi Jewish (ASJ) AF: 0.0295 AC: 741 AN: 25136

East Asian (EAS) AF: 0.00 AC: 0 AN: 35678

South Asian (SAS) AF: 0.0151 AC: 1186 AN: 78764

European-Finnish (FIN) AF: 0.000305 AC: 15 AN: 49226

Middle Eastern (MID) AF: 0.0338 AC: 192 AN: 5686

European-Non Finnish (NFE) AF: 0.00147 AC: 1586 AN: 1078232

Other (OTH) AF: 0.00581 AC: 337 AN: 57954

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

African (AFR) AF: 0.000361 AC: 15 AN: 41534

American (AMR) AF: 0.00360 AC: 55 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.0127 AC: 61 AN: 4818

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10594

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00268 AC: 182 AN: 68000

Other (OTH) AF: 0.00948 AC: 20 AN: 2110

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

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: Silent variant not in splice consensus -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.2
DANN	Benign	0.60
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism

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: rs188496398; hg19: chr1-225340420;