2-195738125-C-T

Variant names:

• chr2-195738125-C-T
• rs116269254
• NM_018897.3:c.11871G>A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_018897.3(DNAH7):​c.11871G>A​(p.Met3957Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000216 in 1,613,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: DNAH7 NM_018897.3 missense, splice_region
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.90

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]

LOC107985972 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013422877).
• BP6: Variant 2-195738125-C-T is Benign according to our data. Variant chr2-195738125-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3049162.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000139 (203/1461194) while in subpopulation AFR AF= 0.00379 (127/33466). AF 95% confidence interval is 0.00326. There are 0 homozygotes in gnomad4_exome. There are 92 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH7	NM_018897.3	c.11871G>A	p.Met3957Ile	missense_variant, splice_region_variant	Exon 65 of 65	ENST00000312428.11	NP_061720.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH7	ENST00000312428.11	c.11871G>A	p.Met3957Ile	missense_variant, splice_region_variant	Exon 65 of 65	1	NM_018897.3	ENSP00000311273.6

Frequencies

GnomAD3 genomes AF: 0.000959 AC: 146 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

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: 0.0000441

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000253 AC: 63 AN: 248530 Hom.: 0 AF XY: 0.000193 AC XY: 26 AN XY: 134818

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.000319

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: 0.0000800

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000139 AC: 203 AN: 1461194 Hom.: 0 Cov.: 31 AF XY: 0.000127 AC XY: 92 AN XY: 726914

Gnomad4 AFR exome AF: 0.00379

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.000958 AC: 146 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.000926 AC XY: 69 AN XY: 74498

Gnomad4 AFR AF: 0.00313

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000269 Hom.: 1

Bravo AF: 0.00109

ESP6500AA AF: 0.00238 AC: 9

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000331 AC: 40

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

DNAH7-related disorder Benign:1

Nov 11, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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	0.18
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.71
DEOGEN2	Benign	0.0075	.;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.87	D;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.3	.;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.19	N;N
REVEL	Benign	0.20
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;.
Polyphen		0.0010	.;B
Vest4		0.28
MutPred		0.58		.;Loss of MoRF binding (P = 0.1141);
MVP		0.12
MPC		0.032
ClinPred		0.017	T
GERP RS		4.5
Varity_R		0.20
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs116269254; hg19: chr2-196602849;