1-224967434-C-T

Variant names:

• chr1-224967434-C-T
• rs375791690
• NM_001367479.1:c.502C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001367479.1(DNAH14):​c.502C>T​(p.Pro168Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00035 in 1,534,062 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (1 hom.)
• Consequence: DNAH14 NM_001367479.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.329
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011823058).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH14	NM_001367479.1	MANE Select	c.502C>T	p.Pro168Ser	missense	Exon 6 of 86	NP_001354408.1
	DNAH14	NM_001145154.3		c.502C>T	p.Pro168Ser	missense	Exon 6 of 11	NP_001138626.1
	DNAH14	NM_001349911.2		c.502C>T	p.Pro168Ser	missense	Exon 6 of 11	NP_001336840.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH14	ENST00000682510.1	MANE Select	c.502C>T	p.Pro168Ser	missense	Exon 6 of 86	ENSP00000508305.1
	DNAH14	ENST00000400952.7	TSL:1	c.502C>T	p.Pro168Ser	missense	Exon 6 of 11	ENSP00000383737.3
	DNAH14	ENST00000366849.5	TSL:1	c.502C>T	p.Pro168Ser	missense	Exon 6 of 11	ENSP00000355814.1

Frequencies

GnomAD3 genomes AF: 0.000239 AC: 36 AN: 150770 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000384

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000311 AC: 61 AN: 196060 AF XY: 0.000287

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000530

Gnomad ASJ exome AF: 0.00197

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000451

Gnomad OTH exome AF: 0.000227

GnomAD4 exome AF: 0.000362 AC: 501 AN: 1383292 Hom.: 1 Cov.: 31 AF XY: 0.000338 AC XY: 232 AN XY: 686592

African (AFR) AF: 0.0000343 AC: 1 AN: 29156

American (AMR) AF: 0.0000348 AC: 1 AN: 28704

Ashkenazi Jewish (ASJ) AF: 0.00218 AC: 51 AN: 23360

East Asian (EAS) AF: 0.00 AC: 0 AN: 36752

South Asian (SAS) AF: 0.00 AC: 0 AN: 70622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5454

European-Non Finnish (NFE) AF: 0.000396 AC: 428 AN: 1081136

Other (OTH) AF: 0.000352 AC: 20 AN: 56816

GnomAD4 genome AF: 0.000239 AC: 36 AN: 150770 Hom.: 0 Cov.: 32 AF XY: 0.000218 AC XY: 16 AN XY: 73522

African (AFR) AF: 0.0000488 AC: 2 AN: 40978

American (AMR) AF: 0.00 AC: 0 AN: 15056

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10288

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

European-Non Finnish (NFE) AF: 0.000384 AC: 26 AN: 67788

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.000627 Hom.: 0

Bravo AF: 0.000223

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000246 AC: 2

ExAC AF: 0.000273 AC: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.9
DANN	Benign	0.95
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.33
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.016
Sift	Benign	0.19	T
Sift4G	Uncertain	0.028	D
Polyphen		0.16	B
Vest4		0.37
MVP		0.11
MPC		0.14
ClinPred		0.019	T
GERP RS		-2.4
Varity_R		0.035
gMVP		0.052
Mutation Taster		=99/1	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: rs375791690; hg19: chr1-225155136; COSMIC: COSV100835866; COSMIC: COSV100835866;