Genetic Variant NM_018897.3:c.12053T>C (chr2-195737943-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_018897.3(DNAH7):c.12053T>C(p.Leu4018Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DNAH7
NM_018897.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.36

Variant links:

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 links:

SLC39A10 (HGNC:20861): (solute carrier family 39 member 10) Zinc is an essential cofactor for hundreds of enzymes. It is involved in protein, nucleic acid, carbohydrate, and lipid metabolism, as well as in the control of gene transcription, growth, development, and differentiation. SLC39A10 belongs to a subfamily of proteins that show structural characteristics of zinc transporters (Taylor and Nicholson, 2003 [PubMed 12659941]).[supplied by OMIM, Mar 2008]

SLC39A10 links:

LOC107985972 (HGNC:):

LOC107985972 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH7	NM_018897.3 link	c.12053T>C	p.Leu4018Pro	missense_variant	Exon 65 of 65	ENST00000312428.11	NP_061720.2	Q8WXX0-1
SLC39A10	NM_020342.3 link	c.*2902A>G		downstream_gene_variant		ENST00000359634.10	NP_065075.1	Q9ULF5-1A0A024R3W5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH7	ENST00000312428.11 link	c.12053T>C	p.Leu4018Pro	missense_variant	Exon 65 of 65	1	NM_018897.3	ENSP00000311273.6		Q8WXX0-1
SLC39A10	ENST00000359634.10 link	c.*2902A>G		downstream_gene_variant		1	NM_020342.3	ENSP00000352655.5		Q9ULF5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249280

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135272

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461724

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727184

show subpopulations

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000827

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.12053T>C (p.L4018P) alteration is located in exon 65 (coding exon 65) of the DNAH7 gene. This alteration results from a T to C substitution at nucleotide position 12053, causing the leucine (L) at amino acid position 4018 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

.;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.017

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Benign

-0.31

MutationAssessor

Pathogenic

4.4

.;H

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-6.3

D;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0020

D;.

Polyphen

1.0

.;D

Vest4

0.89

MutPred

0.90

.;Gain of disorder (P = 0.0305);

MVP

0.26

MPC

0.27

ClinPred

0.99

GERP RS

4.5

Varity_R

0.97

gMVP

0.96

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over