chr7-21861899-T-G

Position:

• chr7-21861899-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001277115.2(DNAH11):​c.11249T>G​(p.Val3750Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,613,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 0.925

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 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=0.015707612).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.11249T>G	p.Val3750Gly	missense_variant	69/82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.11249T>G	p.Val3750Gly	missense_variant	69/82	5	NM_001277115.2	ENSP00000475939	P1
DNAH11	ENST00000421290.1	n.432T>G		non_coding_transcript_exon_variant	4/4	4
DNAH11	ENST00000607413.5	n.512T>G		non_coding_transcript_exon_variant	4/4	4

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000201 AC: 50 AN: 248410 Hom.: 0 AF XY: 0.000185 AC XY: 25 AN XY: 134772

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000220 AC: 321 AN: 1461420 Hom.: 0 Cov.: 30 AF XY: 0.000208 AC XY: 151 AN XY: 726984

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000214

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74434

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000304 Hom.: 0

Bravo AF: 0.000272

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000357 AC: 3

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000436

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 08, 2017	The p.V3750G variant (also known as c.11249T>G), located in coding exon 69 of the DNAH11 gene, results from a T to G substitution at nucleotide position 11249. The valine at codon 3750 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to betolerated by SIFT in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

Primary ciliary dyskinesia 7 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Aug 14, 2023	The DNAH11 c.11249T>G (p.Val3750Gly) variant, to our knowledge, has not been reported in the medical literature in an individual with primary ciliary dyskinesia but has been reported in the ClinVar database as a germline variant of uncertain significance by three submitters and a benign variant by one submitter. The overall minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.02% which is lower than the incidence of autosomal recessive primary ciliary dyskinesia. The valine at this codon is not conserved across vertebrates and computational predictors suggest that the variant does not impact DNAH11 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 11, 2024

Variant summary: DNAH11 c.11249T>G (p.Val3750Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 248410 control chromosomes (gnomAD). To our knowledge, no occurrence of c.11249T>G in individuals affected with Primary Ciliary Dyskinesia 7 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 359677). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.88
DEOGEN2	Benign	0.043	.;.;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.48	T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.016	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.4	.;N;.
REVEL	Benign	0.032
Sift	Benign	0.25	.;T;.
Vest4		0.21
MVP		0.41
ClinPred		0.023	T
GERP RS		0.39
Varity_R		0.060
gMVP		0.37

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: rs199864090; hg19: chr7-21901517;