NM_001366028.2:c.9639G>C

Variant names:

• chr3-57352120-C-G
• rs12053975
• NM_001366028.2:c.9639G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001366028.2(DNAH12):​c.9639G>C​(p.Leu3213Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,527,738 control chromosomes in the GnomAD database, including 45,039 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4503 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40536 hom.)
• Consequence: DNAH12 NM_001366028.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.183
• Publications: 10 publications found

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]

DNAH12 Gene-Disease associations (from GenCC):

• oligoasthenoteratozoospermia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.104).
• BP6: Variant 3-57352120-C-G is Benign according to our data. Variant chr3-57352120-C-G is described in ClinVar as Benign. ClinVar VariationId is 402631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.183 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH12	NM_001366028.2	c.9639G>C	p.Leu3213Leu	synonymous_variant	Exon 60 of 74	ENST00000495027.6	NP_001352957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH12	ENST00000495027.6	c.9639G>C	p.Leu3213Leu	synonymous_variant	Exon 60 of 74	5	NM_001366028.2	ENSP00000418137.2
DNAH12	ENST00000351747.6	c.7035G>C	p.Leu2345Leu	synonymous_variant	Exon 45 of 59	5		ENSP00000295937.3
DNAH12	ENST00000466540.2	c.114G>C	p.Leu38Leu	synonymous_variant	Exon 2 of 15	5		ENSP00000420359.2

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34195 AN: 151848 Hom.: 4501 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.230

GnomAD2 exomes AF: 0.278 AC: 38176 AN: 137390 AF XY: 0.282

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.340

Gnomad EAS exome AF: 0.381

Gnomad FIN exome AF: 0.299

Gnomad NFE exome AF: 0.222

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.233 AC: 321213 AN: 1375770 Hom.: 40536 Cov.: 32 AF XY: 0.238 AC XY: 161343 AN XY: 677544

African (AFR) AF: 0.117 AC: 3540 AN: 30290

American (AMR) AF: 0.323 AC: 9864 AN: 30542

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 8441 AN: 24726

East Asian (EAS) AF: 0.420 AC: 14601 AN: 34758

South Asian (SAS) AF: 0.375 AC: 27100 AN: 72312

European-Finnish (FIN) AF: 0.298 AC: 14648 AN: 49084

Middle Eastern (MID) AF: 0.323 AC: 1820 AN: 5630

European-Non Finnish (NFE) AF: 0.212 AC: 226931 AN: 1071332

Other (OTH) AF: 0.250 AC: 14268 AN: 57096

GnomAD4 genome AF: 0.225 AC: 34207 AN: 151968 Hom.: 4503 Cov.: 32 AF XY: 0.235 AC XY: 17485 AN XY: 74260

African (AFR) AF: 0.119 AC: 4921 AN: 41460

American (AMR) AF: 0.309 AC: 4715 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 1159 AN: 3472

East Asian (EAS) AF: 0.401 AC: 2071 AN: 5164

South Asian (SAS) AF: 0.402 AC: 1940 AN: 4822

European-Finnish (FIN) AF: 0.301 AC: 3159 AN: 10508

Middle Eastern (MID) AF: 0.272 AC: 79 AN: 290

European-Non Finnish (NFE) AF: 0.226 AC: 15345 AN: 67970

Other (OTH) AF: 0.235 AC: 498 AN: 2116

Alfa AF: 0.236 Hom.: 1477

Bravo AF: 0.216

Asia WGS AF: 0.427 AC: 1476 AN: 3462

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
BayesDel_noAF	Benign	-0.37
CADD	Benign	1.2
DANN	Benign	0.71
PhyloP100		-0.18
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12053975; hg19: chr3-57386148; COSMIC: COSV61063437;