1-225381539-T-G

Variant names:

• chr1-225381539-T-G
• rs950210
• NM_001367479.1:c.13037T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001367479.1(DNAH14):​c.13037T>G​(p.Phe4346Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 1,538,778 control chromosomes in the GnomAD database, including 313,741 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (25900 hom., cov: 32)
  • Exomes 𝑓: 0.64 (287841 hom.)
• Consequence: DNAH14 NM_001367479.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.88
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4610508E-6).
• BP6: Variant 1-225381539-T-G is Benign according to our data. Variant chr1-225381539-T-G is described in CliVar as Benign. Clinvar id is 402666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-225381539-T-G is described in CliVar as Benign. Clinvar id is 402666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-225381539-T-G is described in CliVar as Benign. Clinvar id is 402666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-225381539-T-G is described in CliVar as Benign. Clinvar id is 402666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-225381539-T-G is described in CliVar as Benign. Clinvar id is 402666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH14	NM_001367479.1	c.13037T>G	p.Phe4346Cys	missense_variant	Exon 81 of 86	ENST00000682510.1	NP_001354408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH14	ENST00000682510.1	c.13037T>G	p.Phe4346Cys	missense_variant	Exon 81 of 86		NM_001367479.1	ENSP00000508305.1

Frequencies

GnomAD3 genomes AF: 0.553 AC: 84032 AN: 151838 Hom.: 25884 Cov.: 32

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.551

Gnomad AMR AF: 0.712

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.769

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.693

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.655

Gnomad OTH AF: 0.602

GnomAD2 exomes AF: 0.636 AC: 92658 AN: 145582 AF XY: 0.627

Gnomad AFR exome AF: 0.255

Gnomad AMR exome AF: 0.746

Gnomad ASJ exome AF: 0.706

Gnomad EAS exome AF: 0.764

Gnomad FIN exome AF: 0.690

Gnomad NFE exome AF: 0.653

Gnomad OTH exome AF: 0.681

GnomAD4 exome AF: 0.638 AC: 885049 AN: 1386822 Hom.: 287841 Cov.: 37 AF XY: 0.634 AC XY: 433778 AN XY: 684102

African (AFR) AF: 0.238 AC: 7290 AN: 30656

American (AMR) AF: 0.740 AC: 23983 AN: 32422

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 17572 AN: 24920

East Asian (EAS) AF: 0.782 AC: 27878 AN: 35648

South Asian (SAS) AF: 0.473 AC: 36423 AN: 77010

European-Finnish (FIN) AF: 0.690 AC: 33967 AN: 49206

Middle Eastern (MID) AF: 0.685 AC: 3881 AN: 5664

European-Non Finnish (NFE) AF: 0.650 AC: 697486 AN: 1073760

Other (OTH) AF: 0.636 AC: 36569 AN: 57536

GnomAD4 genome AF: 0.553 AC: 84065 AN: 151956 Hom.: 25900 Cov.: 32 AF XY: 0.557 AC XY: 41358 AN XY: 74240

African (AFR) AF: 0.259 AC: 10708 AN: 41404

American (AMR) AF: 0.712 AC: 10876 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 2449 AN: 3470

East Asian (EAS) AF: 0.769 AC: 3973 AN: 5168

South Asian (SAS) AF: 0.462 AC: 2223 AN: 4808

European-Finnish (FIN) AF: 0.693 AC: 7307 AN: 10540

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.655 AC: 44538 AN: 67976

Other (OTH) AF: 0.608 AC: 1285 AN: 2114

Alfa AF: 0.627 Hom.: 118425

Bravo AF: 0.548

TwinsUK AF: 0.643 AC: 2384

ALSPAC AF: 0.656 AC: 2530

ESP6500AA AF: 0.245 AC: 339

ESP6500EA AF: 0.657 AC: 2090

ExAC AF: 0.538 AC: 11275

Asia WGS AF: 0.589 AC: 2047 AN: 3474

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: Frequency -

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
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Benign	0.47
DEOGEN2	Benign	0.030	T;.;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.64	T;T;.
MetaRNN	Benign	0.0000015	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;.
PhyloP100		2.9
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Benign	0.069
Sift	Benign	0.15	T;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.0	.;B;B
Vest4		0.26
ClinPred		0.015	T
GERP RS		1.2
Varity_R		0.15
Mutation Taster		=99/1	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: rs950210; hg19: chr1-225569241; COSMIC: COSV59894181;