rs6768943

Positions:

• chr3-57445261-G-A
• chr3-57445261-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001366028.2(DNAH12):​c.4338C>T​(p.Tyr1446=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 1,550,476 control chromosomes in the GnomAD database, including 210,621 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.45 (16936 hom., cov: 32)
  • Exomes 𝑓: 0.52 (193685 hom.)
• Consequence: DNAH12 NM_001366028.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.378

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 3-57445261-G-A is Benign according to our data. Variant chr3-57445261-G-A is described in ClinVar as [Benign]. Clinvar id is 402637.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.378 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH12	NM_001366028.2	c.4338C>T	p.Tyr1446=	synonymous_variant	28/74	ENST00000495027.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH12	ENST00000495027.6	c.4338C>T	p.Tyr1446=	synonymous_variant	28/74	5	NM_001366028.2	P1
DNAH12	ENST00000351747.6	c.4269C>T	p.Tyr1423=	synonymous_variant	28/59	5

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67692 AN: 151898 Hom.: 16938 Cov.: 32

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.626

Gnomad AMR AF: 0.515

Gnomad ASJ AF: 0.630

Gnomad EAS AF: 0.419

Gnomad SAS AF: 0.591

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.533

Gnomad OTH AF: 0.491

GnomAD3 exomes AF: 0.522 AC: 81365 AN: 155998 Hom.: 22159 AF XY: 0.531 AC XY: 43875 AN XY: 82686

Gnomad AFR exome AF: 0.185

Gnomad AMR exome AF: 0.492

Gnomad ASJ exome AF: 0.635

Gnomad EAS exome AF: 0.410

Gnomad SAS exome AF: 0.586

Gnomad FIN exome AF: 0.600

Gnomad NFE exome AF: 0.534

Gnomad OTH exome AF: 0.535

GnomAD4 exome AF: 0.522 AC: 730033 AN: 1398460 Hom.: 193685 Cov.: 47 AF XY: 0.526 AC XY: 362467 AN XY: 689642

Gnomad4 AFR exome AF: 0.187

Gnomad4 AMR exome AF: 0.497

Gnomad4 ASJ exome AF: 0.634

Gnomad4 EAS exome AF: 0.443

Gnomad4 SAS exome AF: 0.586

Gnomad4 FIN exome AF: 0.596

Gnomad4 NFE exome AF: 0.524

Gnomad4 OTH exome AF: 0.519

GnomAD4 genome AF: 0.445 AC: 67694 AN: 152016 Hom.: 16936 Cov.: 32 AF XY: 0.453 AC XY: 33642 AN XY: 74276

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.514

Gnomad4 ASJ AF: 0.630

Gnomad4 EAS AF: 0.418

Gnomad4 SAS AF: 0.592

Gnomad4 FIN AF: 0.605

Gnomad4 NFE AF: 0.533

Gnomad4 OTH AF: 0.492

Alfa AF: 0.501 Hom.: 10964

Bravo AF: 0.423

Asia WGS AF: 0.523 AC: 1819 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.9
DANN	Benign	0.40

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: rs6768943; hg19: chr3-57430988; COSMIC: COSV61060182;