7-21704421-T-G

Position:

• chr7-21704421-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001277115.2(DNAH11):​c.6274-13T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 1,594,826 control chromosomes in the GnomAD database, including 83,296 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (19302 hom., cov: 32)
  • Exomes 𝑓: 0.26 (63994 hom.)
• Consequence: DNAH11 NM_001277115.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.03

Genes affected

DNAH11 (HGNC:2942): (dynein axonemal heavy chain 11) This gene encodes a ciliary outer dynein arm protein and is a member of the dynein heavy chain family. It is a microtubule-dependent motor ATPase and has been reported to be involved in the movement of respiratory cilia. Mutations in this gene have been implicated in causing Kartagener Syndrome (a combination of situs inversus totalis and Primary Ciliary Dyskinesia (PCD), also called Immotile Cilia Syndrome 1 (ICS1)) and male sterility. [provided by RefSeq, Mar 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-21704421-T-G is Benign according to our data. Variant chr7-21704421-T-G is described in ClinVar as [Benign]. Clinvar id is 163107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21704421-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.6274-13T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.6274-13T>G		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001277115.2	ENSP00000475939	P1

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64308 AN: 151594 Hom.: 19247 Cov.: 32

Gnomad AFR AF: 0.813

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.441

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.739

Gnomad SAS AF: 0.450

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.359

GnomAD3 exomes AF: 0.390 AC: 82505 AN: 211530 Hom.: 20124 AF XY: 0.373 AC XY: 42475 AN XY: 113878

Gnomad AFR exome AF: 0.835

Gnomad AMR exome AF: 0.564

Gnomad ASJ exome AF: 0.193

Gnomad EAS exome AF: 0.758

Gnomad SAS exome AF: 0.459

Gnomad FIN exome AF: 0.296

Gnomad NFE exome AF: 0.223

Gnomad OTH exome AF: 0.317

GnomAD4 exome AF: 0.257 AC: 370622 AN: 1443116 Hom.: 63994 Cov.: 31 AF XY: 0.258 AC XY: 185001 AN XY: 716308

Gnomad4 AFR exome AF: 0.839

Gnomad4 AMR exome AF: 0.524

Gnomad4 ASJ exome AF: 0.174

Gnomad4 EAS exome AF: 0.767

Gnomad4 SAS exome AF: 0.428

Gnomad4 FIN exome AF: 0.274

Gnomad4 NFE exome AF: 0.197

Gnomad4 OTH exome AF: 0.299

GnomAD4 genome AF: 0.425 AC: 64433 AN: 151710 Hom.: 19302 Cov.: 32 AF XY: 0.431 AC XY: 31990 AN XY: 74144

Gnomad4 AFR AF: 0.813

Gnomad4 AMR AF: 0.442

Gnomad4 ASJ AF: 0.175

Gnomad4 EAS AF: 0.738

Gnomad4 SAS AF: 0.451

Gnomad4 FIN AF: 0.275

Gnomad4 NFE AF: 0.200

Gnomad4 OTH AF: 0.362

Alfa AF: 0.290 Hom.: 1788

Bravo AF: 0.453

Asia WGS AF: 0.601 AC: 2088 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	6274-13T>G in intron 37 of DNAH11: This variant is not expected to have clinical significance because it has been identified in 22.0% (807/3666) of African Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs2965401). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 14, 2016	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Primary ciliary dyskinesia 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.3
DANN	Benign	0.58

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: rs2965401; hg19: chr7-21744039;