rs4681982

Variant names:

• chr3-57428344-G-A
• rs4681982
• NM_001366028.2:c.5253+289C>T

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+289C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,166,838 control chromosomes in the GnomAD database, including 130,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (25133 hom., cov: 32)
  • Exomes 𝑓: 0.45 (104935 hom.)
• Consequence: DNAH12 NM_001366028.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.401

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=1.9716767E-6).
• BP6: Variant 3-57428344-G-A is Benign according to our data. Variant chr3-57428344-G-A is described in ClinVar as [Benign]. Clinvar id is 402633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH12	NM_001366028.2	c.5253+289C>T		intron_variant	Intron 34 of 73	ENST00000495027.6	NP_001352957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH12	ENST00000495027.6	c.5253+289C>T		intron_variant	Intron 34 of 73	5	NM_001366028.2	ENSP00000418137.2
DNAH12	ENST00000351747.6	c.5288C>T	p.Thr1763Ile	missense_variant	Exon 35 of 59	5		ENSP00000295937.3

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84968 AN: 151960 Hom.: 25114 Cov.: 32

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.466

Gnomad AMR AF: 0.557

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.421

Gnomad SAS AF: 0.578

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.529

GnomAD3 exomes AF: 0.500 AC: 67160 AN: 134268 Hom.: 17290 AF XY: 0.500 AC XY: 35604 AN XY: 71182

Gnomad AFR exome AF: 0.775

Gnomad AMR exome AF: 0.520

Gnomad ASJ exome AF: 0.448

Gnomad EAS exome AF: 0.414

Gnomad SAS exome AF: 0.562

Gnomad FIN exome AF: 0.505

Gnomad NFE exome AF: 0.460

Gnomad OTH exome AF: 0.486

GnomAD4 exome AF: 0.449 AC: 455352 AN: 1014760 Hom.: 104935 Cov.: 16 AF XY: 0.453 AC XY: 229186 AN XY: 505868

Gnomad4 AFR exome AF: 0.759

Gnomad4 AMR exome AF: 0.514

Gnomad4 ASJ exome AF: 0.431

Gnomad4 EAS exome AF: 0.418

Gnomad4 SAS exome AF: 0.550

Gnomad4 FIN exome AF: 0.505

Gnomad4 NFE exome AF: 0.428

Gnomad4 OTH exome AF: 0.468

GnomAD4 genome AF: 0.559 AC: 85044 AN: 152078 Hom.: 25133 Cov.: 32 AF XY: 0.562 AC XY: 41756 AN XY: 74342

Gnomad4 AFR AF: 0.764

Gnomad4 AMR AF: 0.556

Gnomad4 ASJ AF: 0.428

Gnomad4 EAS AF: 0.420

Gnomad4 SAS AF: 0.579

Gnomad4 FIN AF: 0.510

Gnomad4 NFE AF: 0.461

Gnomad4 OTH AF: 0.530

Alfa AF: 0.470 Hom.: 12007

Bravo AF: 0.566

TwinsUK AF: 0.449 AC: 1665

ALSPAC AF: 0.458 AC: 1765

ExAC AF: 0.511 AC: 10565

Asia WGS AF: 0.552 AC: 1918 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.88
DANN	Benign	0.62
DEOGEN2	Benign	0.0067	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.000070	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0000020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.040
Sift	Benign	0.062	T
Polyphen		0.0	B
Vest4		0.0060
ClinPred		0.0061	T
GERP RS		-0.55
Varity_R		0.039

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: rs4681982; hg19: chr3-57414071; COSMIC: COSV61054136;