chr5-13882749-T-C

Position:

• chr5-13882749-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001369.3(DNAH5):​c.3241A>G​(p.Met1081Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,613,786 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (49 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (56 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.63

Genes affected

DNAH5 (HGNC:2950): (dynein axonemal heavy chain 5) This gene encodes a dynein protein, which is part of a microtubule-associated motor protein complex consisting of heavy, light, and intermediate chains. This protein is an axonemal heavy chain dynein. It functions as a force-generating protein with ATPase activity, whereby the release of ADP is thought to produce the force-producing power stroke. Mutations in this gene cause primary ciliary dyskinesia type 3, as well as Kartagener syndrome, which are both diseases due to ciliary defects. [provided by RefSeq, Oct 2009]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018901825).
• BP6: Variant 5-13882749-T-C is Benign according to our data. Variant chr5-13882749-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 178752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13882749-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0136 (2078/152318) while in subpopulation AFR AF= 0.0459 (1907/41562). AF 95% confidence interval is 0.0442. There are 49 homozygotes in gnomad4. There are 985 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.3241A>G	p.Met1081Val	missense_variant	21/79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.3241A>G	p.Met1081Val	missense_variant	21/79	1	NM_001369.3	ENSP00000265104	P4
	ENST00000503244.2	n.254-13840T>C		intron_variant, non_coding_transcript_variant		4
DNAH5	ENST00000681290.1	c.3196A>G	p.Met1066Val	missense_variant	21/79			ENSP00000505288	A1
	ENST00000637153.1	n.214-13840T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2065 AN: 152200 Hom.: 49 Cov.: 33

Gnomad AFR AF: 0.0457

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0119

GnomAD3 exomes AF: 0.00365 AC: 916 AN: 251170 Hom.: 19 AF XY: 0.00278 AC XY: 378 AN XY: 135772

Gnomad AFR exome AF: 0.0482

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00150 AC: 2195 AN: 1461468 Hom.: 56 Cov.: 32 AF XY: 0.00128 AC XY: 934 AN XY: 727082

Gnomad4 AFR exome AF: 0.0509

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000900

Gnomad4 OTH exome AF: 0.00384

GnomAD4 genome AF: 0.0136 AC: 2078 AN: 152318 Hom.: 49 Cov.: 33 AF XY: 0.0132 AC XY: 985 AN XY: 74492

Gnomad4 AFR AF: 0.0459

Gnomad4 AMR AF: 0.00849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00244 Hom.: 10

Bravo AF: 0.0159

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0411 AC: 181

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00438 AC: 532

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 16, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Primary ciliary dyskinesia 3 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 15, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Met1081Val in exon 21 of DNAH5: This variant is not expected to have clinical si gnificance because it has been identified in 4.1% (181/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs16902880). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2024	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.7
DANN	Benign	0.61
DEOGEN2	Benign	0.034	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.065
Sift	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.21
MPC		0.095
ClinPred		0.0040	T
GERP RS		-1.5
Varity_R		0.063
gMVP		0.21

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: rs16902880; hg19: chr5-13882858;