3-57470644-T-C

Variant names:

• chr3-57470644-T-C
• rs9871422
• NM_001366028.2:c.1912-8A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001366028.2(DNAH12):​c.1912-8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.676 in 1,516,742 control chromosomes in the GnomAD database, including 348,272 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34257 hom., cov: 32)
  • Exomes 𝑓: 0.68 (314015 hom.)
• Consequence: DNAH12 NM_001366028.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002040
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.410
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-57470644-T-C is Benign according to our data. Variant chr3-57470644-T-C is described in ClinVar as Benign. ClinVar VariationId is 402640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.732 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366028.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH12	NM_001366028.2	MANE Select	c.1912-8A>G		splice_region intron	N/A	NP_001352957.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH12	ENST00000495027.6	TSL:5 MANE Select	c.1912-8A>G		splice_region intron	N/A	ENSP00000418137.2
	DNAH12	ENST00000351747.6	TSL:5	c.1912-8A>G		splice_region intron	N/A	ENSP00000295937.3
	DNAH12	ENST00000389536.8	TSL:5	c.1912-8A>G		splice_region intron	N/A	ENSP00000374187.4

Frequencies

GnomAD3 genomes AF: 0.669 AC: 101637 AN: 151954 Hom.: 34249 Cov.: 32

Gnomad AFR AF: 0.641

Gnomad AMI AF: 0.832

Gnomad AMR AF: 0.638

Gnomad ASJ AF: 0.790

Gnomad EAS AF: 0.489

Gnomad SAS AF: 0.752

Gnomad FIN AF: 0.724

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.675

GnomAD2 exomes AF: 0.683 AC: 85726 AN: 125600 AF XY: 0.687

Gnomad AFR exome AF: 0.637

Gnomad AMR exome AF: 0.615

Gnomad ASJ exome AF: 0.798

Gnomad EAS exome AF: 0.478

Gnomad FIN exome AF: 0.728

Gnomad NFE exome AF: 0.684

Gnomad OTH exome AF: 0.680

GnomAD4 exome AF: 0.677 AC: 923708 AN: 1364670 Hom.: 314015 Cov.: 32 AF XY: 0.680 AC XY: 457136 AN XY: 672722

African (AFR) AF: 0.641 AC: 18636 AN: 29084

American (AMR) AF: 0.615 AC: 14316 AN: 23280

Ashkenazi Jewish (ASJ) AF: 0.796 AC: 18955 AN: 23802

East Asian (EAS) AF: 0.519 AC: 18369 AN: 35390

South Asian (SAS) AF: 0.759 AC: 54490 AN: 71792

European-Finnish (FIN) AF: 0.721 AC: 35338 AN: 48988

Middle Eastern (MID) AF: 0.749 AC: 4186 AN: 5588

European-Non Finnish (NFE) AF: 0.674 AC: 720872 AN: 1070024

Other (OTH) AF: 0.680 AC: 38546 AN: 56722

GnomAD4 genome AF: 0.669 AC: 101692 AN: 152072 Hom.: 34257 Cov.: 32 AF XY: 0.672 AC XY: 49939 AN XY: 74322

African (AFR) AF: 0.641 AC: 26569 AN: 41460

American (AMR) AF: 0.637 AC: 9736 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.790 AC: 2742 AN: 3472

East Asian (EAS) AF: 0.489 AC: 2532 AN: 5176

South Asian (SAS) AF: 0.753 AC: 3630 AN: 4822

European-Finnish (FIN) AF: 0.724 AC: 7657 AN: 10572

Middle Eastern (MID) AF: 0.701 AC: 206 AN: 294

European-Non Finnish (NFE) AF: 0.683 AC: 46445 AN: 67988

Other (OTH) AF: 0.674 AC: 1418 AN: 2104

Alfa AF: 0.677 Hom.: 17128

Bravo AF: 0.656

Asia WGS AF: 0.657 AC: 2285 AN: 3478

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.5
DANN	Benign	0.76
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs9871422; hg19: chr3-57456371; COSMIC: COSV61063623;