2-195738087-C-G

Variant names:

• chr2-195738087-C-G
• rs200947523
• NM_018897.3:c.11909G>C

Variant summary

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

The NM_018897.3(DNAH7):​c.11909G>C​(p.Arg3970Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,768 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 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. R3970Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNAH7 NM_018897.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.88
• Publications: 0 publications found

Genes affected

DNAH7 (HGNC:18661): (dynein axonemal heavy chain 7) DNAH7 is a component of the inner dynein arm of ciliary axonemes (Zhang et al., 2002 [PubMed 11877439]).[supplied by OMIM, Mar 2008]

DNAH7 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 50

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: LIMITED Submitted by: King Faisal Specialist Hospital and Research Center

LOC107985972 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018897.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH7	NM_018897.3	MANE Select	c.11909G>C	p.Arg3970Pro	missense	Exon 65 of 65	NP_061720.2	Q8WXX0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH7	ENST00000312428.11	TSL:1 MANE Select	c.11909G>C	p.Arg3970Pro	missense	Exon 65 of 65	ENSP00000311273.6	Q8WXX0-1
	DNAH7	ENST00000409063.5	TSL:1	c.1358G>C	p.Arg453Pro	missense	Exon 10 of 10	ENSP00000386912.1	Q8WXX0-2
	DNAH7	ENST00000438565.1	TSL:3	c.*40G>C		3_prime_UTR	Exon 3 of 3	ENSP00000409732.1	H7C362

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461610 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727122

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111814

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Benign	0.73
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0077	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.9
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Benign	0.12
Sift	Benign	0.34	T
Sift4G	Benign	0.33	T
Polyphen		0.29	B
Vest4		0.58
MutPred		0.49		Loss of MoRF binding (P = 0.0334)
MVP		0.18
MPC		0.041
ClinPred		0.86	D
GERP RS		3.6
Varity_R		0.73
gMVP		0.76
Mutation Taster		=65/35	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: rs200947523; hg19: chr2-196602811;