1-225346646-G-T

Variant names:

• chr1-225346646-G-T
• rs7535953
• NM_001367479.1:c.11288G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001367479.1(DNAH14):​c.11288G>T​(p.Arg3763Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,390,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3763K) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAH14 NM_001367479.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.104
• Publications: 14 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.124791116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH14	NM_001367479.1	c.11288G>T	p.Arg3763Ile	missense_variant	Exon 71 of 86	ENST00000682510.1	NP_001354408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH14	ENST00000682510.1	c.11288G>T	p.Arg3763Ile	missense_variant	Exon 71 of 86		NM_001367479.1	ENSP00000508305.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1390338 Hom.: 0 Cov.: 32 AF XY: 0.00000292 AC XY: 2 AN XY: 685896

African (AFR) AF: 0.00 AC: 0 AN: 31056

American (AMR) AF: 0.00 AC: 0 AN: 34644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24878

East Asian (EAS) AF: 0.00 AC: 0 AN: 35596

South Asian (SAS) AF: 0.00 AC: 0 AN: 78424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4772

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1074278

Other (OTH) AF: 0.00 AC: 0 AN: 57556

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.021	T;.;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.61	T;T;.
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.10
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Benign	0.054
Sift	Uncertain	0.0090	D;D;D
Sift4G	Benign	0.12	T;T;T
Polyphen		0.49	.;P;P
Vest4		0.12
MutPred		0.54		.;Loss of solvent accessibility (P = 6e-04);Loss of solvent accessibility (P = 6e-04);
MVP		0.20
ClinPred		0.24	T
GERP RS		-3.8
Varity_R		0.10
Mutation Taster		=98/2	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: rs7535953; hg19: chr1-225534348;