3-57301848-C-G

Variant names:

• chr3-57301848-C-G
• rs4060726
• NM_001366028.2:c.11281G>C

Variant summary

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

The NM_001366028.2(DNAH12):​c.11281G>C​(p.Gly3761Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3761S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DNAH12 NM_001366028.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.479
• Publications: 26 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: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH12	NM_001366028.2	c.11281G>C	p.Gly3761Arg	missense_variant	Exon 70 of 74	ENST00000495027.6	NP_001352957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH12	ENST00000495027.6	c.11281G>C	p.Gly3761Arg	missense_variant	Exon 70 of 74	5	NM_001366028.2	ENSP00000418137.2
DNAH12	ENST00000351747.6	c.8677G>C	p.Gly2893Arg	missense_variant	Exon 55 of 59	5		ENSP00000295937.3
DNAH12	ENST00000466540.2	c.1618G>C	p.Gly540Arg	missense_variant	Exon 11 of 15	5		ENSP00000420359.2
DNAH12	ENST00000494758.5	n.96-4864G>C		intron_variant	Intron 1 of 4	2		ENSP00000420717.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 63

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.75
DANN	Benign	0.54
DEOGEN2	Benign	0.0032	T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.45	.;N
PhyloP100		-0.48
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.1	.;N
REVEL	Benign	0.25
Sift	Benign	0.40	.;T
Polyphen		0.16	.;B
Vest4		0.38
MutPred		0.43		.;Gain of solvent accessibility (P = 0.0674);
MVP		0.20
ClinPred		0.23	T
GERP RS		2.3
Varity_R		0.19
Mutation Taster		=64/36	polymorphism

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: rs4060726; hg19: chr3-57335876;