7-21901009-G-C

Variant names:

• chr7-21901009-G-C
• NM_001277115.2:c.13306G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001277115.2(DNAH11):​c.13306G>C​(p.Ala4436Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000209 in 1,434,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DNAH11 NM_001277115.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.83

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.13306G>C	p.Ala4436Pro	missense_variant, splice_region_variant	Exon 82 of 82	ENST00000409508.8	NP_001264044.1
CDCA7L	NM_018719.5	c.*1313C>G		3_prime_UTR_variant	Exon 10 of 10	ENST00000406877.8	NP_061189.2
CDCA7L	NM_001127370.3	c.*1313C>G		3_prime_UTR_variant	Exon 11 of 11		NP_001120842.1
CDCA7L	NM_001127371.3	c.*1313C>G		3_prime_UTR_variant	Exon 9 of 9		NP_001120843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.13306G>C	p.Ala4436Pro	missense_variant, splice_region_variant	Exon 82 of 82	5	NM_001277115.2	ENSP00000475939.1
CDCA7L	ENST00000406877	c.*1313C>G		3_prime_UTR_variant	Exon 10 of 10	1	NM_018719.5	ENSP00000383986.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1434164 Hom.: 0 Cov.: 33 AF XY: 0.00000141 AC XY: 1 AN XY: 710920

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000273

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	.;.;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.5	.;D;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	.;D;.
Vest4		0.76
MutPred		0.86		Loss of catalytic residue at A4443 (P = 0.0681);Loss of catalytic residue at A4443 (P = 0.0681);.;
MVP		0.47
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.93
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-21940627;