1-225080404-C-T

Variant names:

• chr1-225080404-C-T
• rs115366080
• NM_001367479.1:c.2792C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001367479.1(DNAH14):​c.2792C>T​(p.Ala931Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000188 in 1,545,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 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. A931D) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: DNAH14 NM_001367479.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.857
• Publications: 7 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050311625).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367479.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH14	NM_001367479.1	MANE Select	c.2792C>T	p.Ala931Val	missense	Exon 19 of 86	NP_001354408.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH14	ENST00000682510.1	MANE Select	c.2792C>T	p.Ala931Val	missense	Exon 19 of 86	ENSP00000508305.1
	DNAH14	ENST00000430092.5	TSL:5	c.2792C>T	p.Ala931Val	missense	Exon 19 of 84	ENSP00000414402.1
	DNAH14	ENST00000439375.6	TSL:5	c.2792C>T	p.Ala931Val	missense	Exon 18 of 83	ENSP00000392061.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152180 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000330 AC: 5 AN: 151610 AF XY: 0.0000501

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000681

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000179 AC: 25 AN: 1393722 Hom.: 0 Cov.: 30 AF XY: 0.0000175 AC XY: 12 AN XY: 686984

African (AFR) AF: 0.0000318 AC: 1 AN: 31476

American (AMR) AF: 0.00 AC: 0 AN: 35110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24702

East Asian (EAS) AF: 0.00 AC: 0 AN: 35692

South Asian (SAS) AF: 0.00 AC: 0 AN: 77960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 0.0000223 AC: 24 AN: 1076262

Other (OTH) AF: 0.00 AC: 0 AN: 57768

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152180 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74328

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 342

Bravo AF: 0.0000453

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000400 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.83
DANN	Benign	0.27
DEOGEN2	Benign	0.0040	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.86
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.023
Sift	Benign	0.15	T
Sift4G	Benign	0.14	T
Polyphen		0.0030	B
Vest4		0.17
MutPred		0.45		Loss of catalytic residue at A931 (P = 0.2216)
MVP		0.055
ClinPred		0.023	T
GERP RS		-1.3
Varity_R		0.031
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs115366080; hg19: chr1-225268106;