rs4462937

Positions:

• chr3-57428707-A-G

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.5179T>C​(p.Tyr1727His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,550,806 control chromosomes in the GnomAD database, including 51,843 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4957 hom., cov: 32)
  • Exomes 𝑓: 0.25 (46886 hom.)
• Consequence: DNAH12 NM_001366028.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.178

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=4.0507317E-4).
• BP6: Variant 3-57428707-A-G is Benign according to our data. Variant chr3-57428707-A-G is described in ClinVar as [Benign]. Clinvar id is 402635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) 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.5179T>C	p.Tyr1727His	missense_variant	34/74	ENST00000495027.6	NP_001352957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH12	ENST00000495027.6	c.5179T>C	p.Tyr1727His	missense_variant	34/74	5	NM_001366028.2	ENSP00000418137	P1
DNAH12	ENST00000351747.6	c.5110T>C	p.Tyr1704His	missense_variant	34/59	5		ENSP00000295937

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36416 AN: 152006 Hom.: 4955 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.396

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.242

GnomAD3 exomes AF: 0.300 AC: 45963 AN: 153290 Hom.: 7457 AF XY: 0.306 AC XY: 24912 AN XY: 81314

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.339

Gnomad ASJ exome AF: 0.341

Gnomad EAS exome AF: 0.410

Gnomad SAS exome AF: 0.417

Gnomad FIN exome AF: 0.303

Gnomad NFE exome AF: 0.236

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.250 AC: 349419 AN: 1398680 Hom.: 46886 Cov.: 36 AF XY: 0.255 AC XY: 176028 AN XY: 689778

Gnomad4 AFR exome AF: 0.140

Gnomad4 AMR exome AF: 0.337

Gnomad4 ASJ exome AF: 0.340

Gnomad4 EAS exome AF: 0.440

Gnomad4 SAS exome AF: 0.413

Gnomad4 FIN exome AF: 0.301

Gnomad4 NFE exome AF: 0.226

Gnomad4 OTH exome AF: 0.265

GnomAD4 genome AF: 0.239 AC: 36428 AN: 152126 Hom.: 4957 Cov.: 32 AF XY: 0.250 AC XY: 18568 AN XY: 74348

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.319

Gnomad4 ASJ AF: 0.330

Gnomad4 EAS AF: 0.418

Gnomad4 SAS AF: 0.436

Gnomad4 FIN AF: 0.305

Gnomad4 NFE AF: 0.236

Gnomad4 OTH AF: 0.246

Alfa AF: 0.247 Hom.: 10316

Bravo AF: 0.230

TwinsUK AF: 0.227 AC: 842

ALSPAC AF: 0.228 AC: 879

ESP6500AA AF: 0.141 AC: 195

ESP6500EA AF: 0.239 AC: 759

ExAC AF: 0.298 AC: 6456

Asia WGS AF: 0.454 AC: 1579 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	0.11
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.9
DANN	Benign	0.12
DEOGEN2	Benign	0.0019	T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.26	T;T
MetaRNN	Benign	0.00041	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.4	.;N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	3.0	N;N
REVEL	Benign	0.022
Sift	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.052
ClinPred		0.00033	T
GERP RS		-1.9
Varity_R		0.036

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs4462937; hg19: chr3-57414434; COSMIC: COSV61056340;