1-224967434-C-T

Position:

• chr1-224967434-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 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. 13/20 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011823058).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH14	NM_001367479.1	c.502C>T	p.Pro168Ser	missense_variant	6/86	ENST00000682510.1	NP_001354408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH14	ENST00000682510.1	c.502C>T	p.Pro168Ser	missense_variant	6/86		NM_001367479.1	ENSP00000508305	P1

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

GnomAD3 exomes AF: 0.000311 AC: 61 AN: 196060 Hom.: 0 AF XY: 0.000287 AC XY: 31 AN XY: 108128

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 SAS 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

Gnomad4 AFR exome AF: 0.0000343

Gnomad4 AMR exome AF: 0.0000348

Gnomad4 ASJ exome AF: 0.00218

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000396

Gnomad4 OTH exome AF: 0.000352

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

Gnomad4 AFR AF: 0.0000488

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000384

Gnomad4 OTH AF: 0.00

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

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 24, 2022	The c.502C>T (p.P168S) alteration is located in exon 6 (coding exon 5) of the DNAH14 gene. This alteration results from a C to T substitution at nucleotide position 502, causing the proline (P) at amino acid position 168 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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: Axonemal dynein, but no disease association and no suspicious second variant -

Computational scores

Source: dbNSFP v4.3

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;T;T;T;T;.;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.012	T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.8	N;N;D;D;D;D;N
REVEL	Benign	0.016
Sift	Benign	0.19	T;T;D;T;T;D;T
Sift4G	Uncertain	0.028	D;D;T;T;T;T;D
Polyphen		0.16	B;B;B;B;.;B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs375791690; hg19: chr1-225155136; COSMIC: COSV100835866; COSMIC: COSV100835866;