rs17793014

Positions:

• chr3-57428370-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001366028.2(DNAH12):​c.5253+263A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.401 in 1,340,342 control chromosomes in the GnomAD database, including 113,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8899 hom., cov: 33)
  • Exomes 𝑓: 0.41 (104539 hom.)
• Consequence: DNAH12 NM_001366028.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.272

Genes affected

DNAH12 (HGNC:2943): (dynein axonemal heavy chain 12) Predicted to enable several functions, including ATP binding activity; dynein intermediate chain binding activity; and dynein light intermediate chain binding activity. Predicted to be involved in microtubule-based movement. Predicted to be located in cilium; cytoplasm; and microtubule. Predicted to be part of dynein complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.2354417E-4).
• BP6: Variant 3-57428370-T-A is Benign according to our data. Variant chr3-57428370-T-A is described in ClinVar as [Benign]. Clinvar id is 402634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH12	NM_001366028.2	c.5253+263A>T		intron_variant		ENST00000495027.6	NP_001352957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH12	ENST00000495027.6	c.5253+263A>T		intron_variant		5	NM_001366028.2	ENSP00000418137	P1
DNAH12	ENST00000351747.6	c.5262A>T	p.Lys1754Asn	missense_variant	35/59	5		ENSP00000295937

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48640 AN: 152000 Hom.: 8906 Cov.: 33

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.412

Gnomad EAS AF: 0.0768

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.344

GnomAD3 exomes AF: 0.339 AC: 49201 AN: 144964 Hom.: 9501 AF XY: 0.347 AC XY: 26637 AN XY: 76752

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.400

Gnomad EAS exome AF: 0.0622

Gnomad SAS exome AF: 0.366

Gnomad FIN exome AF: 0.407

Gnomad NFE exome AF: 0.422

Gnomad OTH exome AF: 0.369

GnomAD4 exome AF: 0.412 AC: 489367 AN: 1188224 Hom.: 104539 Cov.: 20 AF XY: 0.411 AC XY: 241572 AN XY: 587254

Gnomad4 AFR exome AF: 0.165

Gnomad4 AMR exome AF: 0.226

Gnomad4 ASJ exome AF: 0.412

Gnomad4 EAS exome AF: 0.0763

Gnomad4 SAS exome AF: 0.372

Gnomad4 FIN exome AF: 0.405

Gnomad4 NFE exome AF: 0.437

Gnomad4 OTH exome AF: 0.385

GnomAD4 genome AF: 0.320 AC: 48657 AN: 152118 Hom.: 8899 Cov.: 33 AF XY: 0.316 AC XY: 23516 AN XY: 74352

Gnomad4 AFR AF: 0.166

Gnomad4 AMR AF: 0.257

Gnomad4 ASJ AF: 0.412

Gnomad4 EAS AF: 0.0768

Gnomad4 SAS AF: 0.342

Gnomad4 FIN AF: 0.400

Gnomad4 NFE AF: 0.425

Gnomad4 OTH AF: 0.339

Alfa AF: 0.394 Hom.: 3997

Bravo AF: 0.301

TwinsUK AF: 0.436 AC: 1618

ALSPAC AF: 0.427 AC: 1645

ExAC AF: 0.348 AC: 7163

Asia WGS AF: 0.209 AC: 728 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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 -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.1
DANN	Benign	0.22
DEOGEN2	Benign	0.0033	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0074	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.00092	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.63	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.015
Sift	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.077
MutPred		0.25		Loss of ubiquitination at K1754 (P = 0.0192);
ClinPred		0.00048	T
GERP RS		-2.6
Varity_R		0.049

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

Other links and lift over

dbSNP: rs17793014; hg19: chr3-57414097; COSMIC: COSV61054147;