NM_001367479.1:c.12593T>C

Variant names:

• chr1-225377313-T-C
• rs3856154
• NM_001367479.1:c.12593T>C

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.12593T>C​(p.Leu4198Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 1,548,846 control chromosomes in the GnomAD database, including 317,763 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (27332 hom., cov: 32)
  • Exomes 𝑓: 0.64 (290431 hom.)
• Consequence: DNAH14 NM_001367479.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.80
• Publications: 28 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
• primary ciliary dyskinesia

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.33696E-6).
• BP6: Variant 1-225377313-T-C is Benign according to our data. Variant chr1-225377313-T-C is described in ClinVar as Benign. ClinVar VariationId is 402664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

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.12593T>C	p.Leu4198Pro	missense	Exon 79 of 86	NP_001354408.1	A0A804HLD3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH14	ENST00000682510.1	MANE Select	c.12593T>C	p.Leu4198Pro	missense	Exon 79 of 86	ENSP00000508305.1	A0A804HLD3
	DNAH14	ENST00000327794.10	TSL:1	n.*804T>C		non_coding_transcript_exon	Exon 34 of 40	ENSP00000328980.6	H7BXS7
	DNAH14	ENST00000327794.10	TSL:1	n.*804T>C		3_prime_UTR	Exon 34 of 40	ENSP00000328980.6	H7BXS7

Frequencies

GnomAD3 genomes AF: 0.581 AC: 88326 AN: 151904 Hom.: 27315 Cov.: 32

Gnomad AFR AF: 0.356

Gnomad AMI AF: 0.550

Gnomad AMR AF: 0.726

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.764

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.694

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.656

Gnomad OTH AF: 0.623

GnomAD2 exomes AF: 0.638 AC: 97070 AN: 152100 AF XY: 0.626

Gnomad AFR exome AF: 0.346

Gnomad AMR exome AF: 0.746

Gnomad ASJ exome AF: 0.703

Gnomad EAS exome AF: 0.759

Gnomad FIN exome AF: 0.689

Gnomad NFE exome AF: 0.651

Gnomad OTH exome AF: 0.682

GnomAD4 exome AF: 0.640 AC: 894053 AN: 1396824 Hom.: 290431 Cov.: 46 AF XY: 0.635 AC XY: 437648 AN XY: 688832

African (AFR) AF: 0.331 AC: 10456 AN: 31544

American (AMR) AF: 0.745 AC: 26359 AN: 35392

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 17717 AN: 25148

East Asian (EAS) AF: 0.780 AC: 27780 AN: 35618

South Asian (SAS) AF: 0.469 AC: 36902 AN: 78634

European-Finnish (FIN) AF: 0.690 AC: 33980 AN: 49236

Middle Eastern (MID) AF: 0.690 AC: 3931 AN: 5696

European-Non Finnish (NFE) AF: 0.649 AC: 699869 AN: 1077668

Other (OTH) AF: 0.640 AC: 37059 AN: 57888

GnomAD4 genome AF: 0.581 AC: 88371 AN: 152022 Hom.: 27332 Cov.: 32 AF XY: 0.585 AC XY: 43442 AN XY: 74322

African (AFR) AF: 0.355 AC: 14720 AN: 41420

American (AMR) AF: 0.726 AC: 11101 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 2451 AN: 3472

East Asian (EAS) AF: 0.765 AC: 3956 AN: 5174

South Asian (SAS) AF: 0.461 AC: 2221 AN: 4814

European-Finnish (FIN) AF: 0.694 AC: 7331 AN: 10566

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

European-Non Finnish (NFE) AF: 0.656 AC: 44559 AN: 67976

Other (OTH) AF: 0.629 AC: 1325 AN: 2106

Alfa AF: 0.639 Hom.: 136746

Bravo AF: 0.580

TwinsUK AF: 0.643 AC: 2385

ALSPAC AF: 0.656 AC: 2529

ESP6500AA AF: 0.342 AC: 474

ESP6500EA AF: 0.657 AC: 2091

ExAC AF: 0.542 AC: 11668

Asia WGS AF: 0.590 AC: 2052 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.040
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	14
DANN	Benign	0.90
DEOGEN2	Benign	0.00080	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.00024	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N
PhyloP100		1.8
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.061
Sift	Benign	0.33	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.041
ClinPred		0.0032	T
GERP RS		4.3
Varity_R		0.071
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: rs3856154; hg19: chr1-225565015; COSMIC: COSV107392554;