rs72658840

chr7-21901250-C-T

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.13547C>T(p.Ala4516Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00536 in 1,601,468 control chromosomes in the GnomAD database, including 310 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A4516A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.026 (170 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (140 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.62

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]

CDCA7L (HGNC:30777): (cell division cycle associated 7 like) Acts upstream of or within positive regulation of cell population proliferation. Located in cytosol; fibrillar center; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014667213).
• BP6: Variant 7-21901250-C-T is Benign according to our data. Variant chr7-21901250-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 226582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21901250-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0862 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.13547C>T	p.Ala4516Val	missense_variant	82/82	ENST00000409508.8
CDCA7L	NM_018719.5	c.*1072G>A		3_prime_UTR_variant	10/10	ENST00000406877.8
CDCA7L	NM_001127370.3	c.*1072G>A		3_prime_UTR_variant	11/11
CDCA7L	NM_001127371.3	c.*1072G>A		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.13547C>T	p.Ala4516Val	missense_variant	82/82	5	NM_001277115.2	P1
CDCA7L	ENST00000406877.8	c.*1072G>A		3_prime_UTR_variant	10/10	1	NM_018719.5	P1
CDCA7L	ENST00000356195.9	c.*1072G>A		3_prime_UTR_variant	11/11	2
CDCA7L	ENST00000488845.1	n.1594G>A		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.0262 AC: 3847 AN: 146778 Hom.: 169 Cov.: 32

Gnomad AFR AF: 0.0888

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00951

Gnomad ASJ AF: 0.00180

Gnomad EAS AF: 0.000609

Gnomad SAS AF: 0.00193

Gnomad FIN AF: 0.000194

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.000931

Gnomad OTH AF: 0.0189

GnomAD3 exomes AF: 0.00685 AC: 1641 AN: 239448 Hom.: 64 AF XY: 0.00522 AC XY: 677 AN XY: 129758

Gnomad AFR exome AF: 0.0867

Gnomad AMR exome AF: 0.00476

Gnomad ASJ exome AF: 0.00157

Gnomad EAS exome AF: 0.000113

Gnomad SAS exome AF: 0.000600

Gnomad FIN exome AF: 0.000142

Gnomad NFE exome AF: 0.000818

Gnomad OTH exome AF: 0.00462

GnomAD4 exome AF: 0.00325 AC: 4724 AN: 1454598 Hom.: 140 Cov.: 33 AF XY: 0.00282 AC XY: 2040 AN XY: 722758

Gnomad4 AFR exome AF: 0.0855

Gnomad4 AMR exome AF: 0.00532

Gnomad4 ASJ exome AF: 0.00171

Gnomad4 EAS exome AF: 0.000355

Gnomad4 SAS exome AF: 0.000758

Gnomad4 FIN exome AF: 0.000226

Gnomad4 NFE exome AF: 0.000950

Gnomad4 OTH exome AF: 0.00719

GnomAD4 genome AF: 0.0262 AC: 3855 AN: 146870 Hom.: 170 Cov.: 32 AF XY: 0.0247 AC XY: 1775 AN XY: 71742

Gnomad4 AFR AF: 0.0886

Gnomad4 AMR AF: 0.00949

Gnomad4 ASJ AF: 0.00180

Gnomad4 EAS AF: 0.000610

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000194

Gnomad4 NFE AF: 0.000931

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0141 Hom.: 30

Bravo AF: 0.0285

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0761 AC: 301

ESP6500EA AF: 0.00144 AC: 12

ExAC AF: 0.00768 AC: 928

Asia WGS AF: 0.0240 AC: 84 AN: 3478

ClinVar

Significance: Benign/Likely 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ala4516Val in exon 82 of DNAH11: This variant is not expected to have clinical s ignificance because it has been identified in 7.6% (301/3954) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs72658840). -

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Primary ciliary dyskinesia 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 03, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	15
Dann	Benign	0.97
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.79	T;T;T
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.96	N;N;N
PrimateAI	Benign	0.40	T
Vest4		0.12
MVP		0.014
ClinPred		0.0098	T
GERP RS		3.8
Varity_R		0.047
gMVP		0.17

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: rs72658840; hg19: chr7-21940868;