chr3-57309182-C-A

Variant names:

• chr3-57309182-C-A
• rs2061535604
• NM_001366028.2:c.11158G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001366028.2(DNAH12):​c.11158G>T​(p.Val3720Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,396,772 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAH12 NM_001366028.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.11158G>T	p.Val3720Leu	missense	Exon 69 of 74	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.11158G>T	p.Val3720Leu	missense	Exon 69 of 74	ENSP00000418137.2	E9PG32
	DNAH12	ENST00000351747.6	TSL:5	c.8554G>T	p.Val2852Leu	missense	Exon 54 of 59	ENSP00000295937.3	Q6ZR08-1
	DNAH12	ENST00000466540.2	TSL:5	c.1495G>T	p.Val499Leu	missense	Exon 10 of 15	ENSP00000420359.2	H7C5N3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1396772 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 688848

African (AFR) AF: 0.00 AC: 0 AN: 31534

American (AMR) AF: 0.00 AC: 0 AN: 35056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25130

East Asian (EAS) AF: 0.00 AC: 0 AN: 35594

South Asian (SAS) AF: 0.00 AC: 0 AN: 78462

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078282

Other (OTH) AF: 0.00 AC: 0 AN: 57876

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		6.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.72		Gain of glycosylation at S2848 (P = 0.0789)
MVP		0.66
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.91
Mutation Taster		=23/77	disease causing

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

Other links and lift over

dbSNP: rs2061535604; hg19: chr3-57343210;