rs6445902

chr3-57508411-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001366028.2(DNAH12):c.672T>G(p.Asp224Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,605,692 control chromosomes in the GnomAD database, including 33,301 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (6410 hom., cov: 32)
  • Exomes 𝑓: 0.18 (26891 hom.)
• Consequence: DNAH12 NM_001366028.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.396

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.632307E-4).
• BP6: Variant 3-57508411-A-C is Benign according to our data. Variant chr3-57508411-A-C is described in ClinVar as [Benign]. Clinvar id is 402643.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH12	NM_001366028.2	c.672T>G	p.Asp224Glu	missense_variant	7/74	ENST00000495027.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH12	ENST00000495027.6	c.672T>G	p.Asp224Glu	missense_variant	7/74	5	NM_001366028.2	P1

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38740 AN: 151934 Hom.: 6393 Cov.: 32

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.0677

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.222

GnomAD3 exomes AF: 0.179 AC: 43599 AN: 243238 Hom.: 4871 AF XY: 0.176 AC XY: 23140 AN XY: 131530

Gnomad AFR exome AF: 0.473

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.0573

Gnomad SAS exome AF: 0.189

Gnomad FIN exome AF: 0.155

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.173

GnomAD4 exome AF: 0.184 AC: 267524 AN: 1453640 Hom.: 26891 Cov.: 32 AF XY: 0.183 AC XY: 132306 AN XY: 722886

Gnomad4 AFR exome AF: 0.480

Gnomad4 AMR exome AF: 0.120

Gnomad4 ASJ exome AF: 0.202

Gnomad4 EAS exome AF: 0.0761

Gnomad4 SAS exome AF: 0.186

Gnomad4 FIN exome AF: 0.154

Gnomad4 NFE exome AF: 0.182

Gnomad4 OTH exome AF: 0.188

GnomAD4 genome AF: 0.255 AC: 38792 AN: 152052 Hom.: 6410 Cov.: 32 AF XY: 0.250 AC XY: 18554 AN XY: 74352

Gnomad4 AFR AF: 0.471

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.203

Gnomad4 EAS AF: 0.0676

Gnomad4 SAS AF: 0.174

Gnomad4 FIN AF: 0.146

Gnomad4 NFE AF: 0.187

Gnomad4 OTH AF: 0.220

Alfa AF: 0.191 Hom.: 7929

Bravo AF: 0.266

TwinsUK AF: 0.193 AC: 717

ALSPAC AF: 0.182 AC: 700

ESP6500AA AF: 0.470 AC: 2073

ESP6500EA AF: 0.190 AC: 1636

ExAC AF: 0.186 AC: 22618

EpiCase AF: 0.176

EpiControl AF: 0.176

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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	7.4
Dann	Benign	0.91
DEOGEN2	Benign	0.0049	T;T;.;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.57	T;T;T;T
MetaRNN	Benign	0.00036	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.75	N;N;N;N
REVEL	Benign	0.022
Sift	Benign	0.39	T;T;T;T
Polyphen		0.0090, 0.45	.;B;.;B
Vest4		0.026
MutPred		0.23		Gain of glycosylation at T221 (P = 0.0582);Gain of glycosylation at T221 (P = 0.0582);Gain of glycosylation at T221 (P = 0.0582);Gain of glycosylation at T221 (P = 0.0582);
MPC		0.077
ClinPred		0.0030	T
GERP RS		-0.56
Varity_R		0.034
gMVP		0.10

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: rs6445902; hg19: chr3-57494138; COSMIC: COSV60857772; COSMIC: COSV60857772;