rs6719500

Variant names:

• chr2-195960678-T-C
• rs6719500
• NM_018897.3:c.2473A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018897.3(DNAH7):​c.2473A>G​(p.Lys825Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,614,048 control chromosomes in the GnomAD database, including 15,671 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2458 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13213 hom.)
• Consequence: DNAH7 NM_018897.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.42
• Publications: 21 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: 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004545808).
• BP6: Variant 2-195960678-T-C is Benign according to our data. Variant chr2-195960678-T-C is described in ClinVar as Benign. ClinVar VariationId is 1225183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH7	NM_018897.3	c.2473A>G	p.Lys825Glu	missense_variant	Exon 18 of 65	ENST00000312428.11	NP_061720.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH7	ENST00000312428.11	c.2473A>G	p.Lys825Glu	missense_variant	Exon 18 of 65	1	NM_018897.3	ENSP00000311273.6

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25490 AN: 152078 Hom.: 2454 Cov.: 32

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.0720

Gnomad SAS AF: 0.0974

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.171

GnomAD2 exomes AF: 0.131 AC: 32703 AN: 249464 AF XY: 0.129

Gnomad AFR exome AF: 0.279

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.148

Gnomad EAS exome AF: 0.0709

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.136

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.130 AC: 190592 AN: 1461852 Hom.: 13213 Cov.: 33 AF XY: 0.129 AC XY: 94110 AN XY: 727228

African (AFR) AF: 0.282 AC: 9425 AN: 33480

American (AMR) AF: 0.122 AC: 5477 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3943 AN: 26136

East Asian (EAS) AF: 0.0615 AC: 2441 AN: 39698

South Asian (SAS) AF: 0.0962 AC: 8295 AN: 86258

European-Finnish (FIN) AF: 0.111 AC: 5945 AN: 53412

Middle Eastern (MID) AF: 0.185 AC: 1067 AN: 5768

European-Non Finnish (NFE) AF: 0.131 AC: 145801 AN: 1111982

Other (OTH) AF: 0.136 AC: 8198 AN: 60394

GnomAD4 genome AF: 0.168 AC: 25531 AN: 152196 Hom.: 2458 Cov.: 32 AF XY: 0.166 AC XY: 12318 AN XY: 74406

African (AFR) AF: 0.269 AC: 11148 AN: 41500

American (AMR) AF: 0.150 AC: 2292 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 517 AN: 3470

East Asian (EAS) AF: 0.0726 AC: 376 AN: 5182

South Asian (SAS) AF: 0.0977 AC: 471 AN: 4822

European-Finnish (FIN) AF: 0.109 AC: 1153 AN: 10606

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9059 AN: 68008

Other (OTH) AF: 0.169 AC: 358 AN: 2116

Alfa AF: 0.148 Hom.: 5774

Bravo AF: 0.177

TwinsUK AF: 0.131 AC: 484

ALSPAC AF: 0.133 AC: 513

ESP6500AA AF: 0.270 AC: 1017

ESP6500EA AF: 0.136 AC: 1118

ExAC AF: 0.134 AC: 16229

Asia WGS AF: 0.0960 AC: 334 AN: 3478

EpiCase AF: 0.149

EpiControl AF: 0.149

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DNAH7-related disorder Benign:1

Aug 31, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Benign	0.24
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N
PhyloP100		3.4
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.095
Sift	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.13
MPC		0.036
ClinPred		0.016	T
GERP RS		5.7
Varity_R		0.11
gMVP		0.23
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6719500; hg19: chr2-196825402; COSMIC: COSV107351554;