3-57402387-T-G

Variant names:

• chr3-57402387-T-G
• rs6445873
• NM_001366028.2:c.6948+922A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001366028.2(DNAH12):​c.6948+922A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000868 in 1,152,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: DNAH12 NM_001366028.2 intron
• Scores: Splicing: ADA: 0.9462
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0150
• Publications: 0 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):

• spermatogenic failure

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• oligoasthenoteratozoospermia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH12	NM_001366028.2	MANE Select	c.6948+922A>C		intron	N/A	NP_001352957.1	E9PG32

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH12	ENST00000495027.6	TSL:5 MANE Select	c.6948+922A>C		intron	N/A	ENSP00000418137.2	E9PG32
	DNAH12	ENST00000351747.6	TSL:5	c.6929+5A>C		splice_region intron	N/A	ENSP00000295937.3	Q6ZR08-1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 8.68e-7 AC: 1 AN: 1152416 Hom.: 0 Cov.: 33 AF XY: 0.00000177 AC XY: 1 AN XY: 565102

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24390

American (AMR) AF: 0.00 AC: 0 AN: 28234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15934

East Asian (EAS) AF: 0.00 AC: 0 AN: 12840

South Asian (SAS) AF: 0.0000131 AC: 1 AN: 76146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4400

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 920440

Other (OTH) AF: 0.00 AC: 0 AN: 41600

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.4
PhyloP100		-0.015

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Benign	0.31
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: rs6445873; hg19: chr3-57388114;