rs144390858

Positions:

• chr2-196001709-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_018897.3(DNAH7):​c.1139T>G​(p.Met380Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,592,638 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (5 hom., cov: 32)
  • Exomes 𝑓: 0.011 (121 hom.)
• Consequence: DNAH7 NM_018897.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 8.14

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011102408).
• BP6: Variant 2-196001709-A-C is Benign according to our data. Variant chr2-196001709-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 402759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-196001709-A-C is described in Lovd as [Benign]. Variant chr2-196001709-A-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH7	NM_018897.3	c.1139T>G	p.Met380Arg	missense_variant	11/65	ENST00000312428.11	NP_061720.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH7	ENST00000312428.11	c.1139T>G	p.Met380Arg	missense_variant	11/65	1	NM_018897.3	ENSP00000311273.6
DNAH7	ENST00000410072.5	c.1139T>G	p.Met380Arg	missense_variant	11/13	2		ENSP00000386260.1

Frequencies

GnomAD3 genomes AF: 0.00896 AC: 1363 AN: 152194 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00726

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00925 AC: 2176 AN: 235326 Hom.: 12 AF XY: 0.00931 AC XY: 1189 AN XY: 127658

Gnomad AFR exome AF: 0.000935

Gnomad AMR exome AF: 0.00857

Gnomad ASJ exome AF: 0.0137

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00394

Gnomad FIN exome AF: 0.00734

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.0166

GnomAD4 exome AF: 0.0114 AC: 16396 AN: 1440326 Hom.: 121 Cov.: 33 AF XY: 0.0112 AC XY: 8022 AN XY: 714980

Gnomad4 AFR exome AF: 0.00171

Gnomad4 AMR exome AF: 0.00861

Gnomad4 ASJ exome AF: 0.0119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00395

Gnomad4 FIN exome AF: 0.00841

Gnomad4 NFE exome AF: 0.0128

Gnomad4 OTH exome AF: 0.0126

GnomAD4 genome AF: 0.00894 AC: 1361 AN: 152312 Hom.: 5 Cov.: 32 AF XY: 0.00818 AC XY: 609 AN XY: 74480

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.00726

Gnomad4 NFE AF: 0.0136

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0119 Hom.: 10

Bravo AF: 0.00869

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00159 AC: 6

ESP6500EA AF: 0.0137 AC: 113

ExAC AF: 0.00900 AC: 1088

Asia WGS AF: 0.00202 AC: 7 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

DNAH7-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 02, 2020

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	Pathogenic	0.90
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0050	.;D
Polyphen		0.90	P;.
Vest4		0.87
MVP		0.33
MPC		0.075
ClinPred		0.064	T
GERP RS		5.7
Varity_R		0.91
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs144390858; hg19: chr2-196866433;