7-21901250-C-A

Variant names:

• chr7-21901250-C-A
• rs72658840
• NM_001277115.2:c.13547C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001277115.2(DNAH11):​c.13547C>A​(p.Ala4516Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4516V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.62
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11801064).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001277115.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	NM_001277115.2	MANE Select	c.13547C>A	p.Ala4516Glu	missense	Exon 82 of 82	NP_001264044.1
	CDCA7L	NM_018719.5	MANE Select	c.*1072G>T		3_prime_UTR	Exon 10 of 10	NP_061189.2
	CDCA7L	NM_001127370.3		c.*1072G>T		3_prime_UTR	Exon 11 of 11	NP_001120842.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	ENST00000409508.8	TSL:5 MANE Select	c.13547C>A	p.Ala4516Glu	missense	Exon 82 of 82	ENSP00000475939.1
	CDCA7L	ENST00000406877.8	TSL:1 MANE Select	c.*1072G>T		3_prime_UTR	Exon 10 of 10	ENSP00000383986.3
	CDCA7L	ENST00000488845.1	TSL:2	n.1594G>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454608 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 722762

African (AFR) AF: 0.00 AC: 0 AN: 33276

American (AMR) AF: 0.00 AC: 0 AN: 44346

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25768

East Asian (EAS) AF: 0.00 AC: 0 AN: 39458

South Asian (SAS) AF: 0.00 AC: 0 AN: 84428

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108332

Other (OTH) AF: 0.00 AC: 0 AN: 60058

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.6
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.11
Sift	Uncertain	0.0050	D
Vest4		0.32
MutPred		0.34		Gain of solvent accessibility (P = 0.0456)
MVP		0.040
ClinPred		0.80	D
GERP RS		3.8
Varity_R		0.11
gMVP		0.40
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs72658840; hg19: chr7-21940868;