Genetic Variant DNAH1:c.4686-3C>T (chr3-52361161-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015512.5(DNAH1):c.4686-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DNAH1
NM_015512.5 splice_region, intron

Scores

Splicing: ADA: 0.0008101

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.306

Publications

0 publications found

Variant links:

Genes affected

DNAH1 (HGNC:2940): (dynein axonemal heavy chain 1) This gene encodes an inner dynein arm heavy chain that provides structural support between the radial spokes and the outer doublet of the sperm tail. Naturally occurring mutations in this gene are associated with primary ciliary dyskinesia and multiple morphological anomalies of the flagella that result in asthenozoospermia and male infertility. Mice with a homozygous knockout of the orthologous gene are viable but have reduced sperm motility and are infertile. [provided by RefSeq, Feb 2017]

DNAH1 Gene-Disease associations (from GenCC):

spermatogenic failure 18
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
ciliary dyskinesia, primary, 37
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
non-syndromic male infertility due to sperm motility disorder
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DNAH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=-0.67).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
DNAH1	NM_015512.5 link	c.4686-3C>T	splice_region_variant, intron_variant	Intron 28 of 77	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2 link	c.4686-3C>T	splice_region_variant, intron_variant	Intron 29 of 79		XP_016861618.1
DNAH1	XM_017006130.2 link	c.4686-3C>T	splice_region_variant, intron_variant	Intron 29 of 78		XP_016861619.1
DNAH1	XM_017006131.2 link	c.4686-3C>T	splice_region_variant, intron_variant	Intron 29 of 78		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
DNAH1	ENST00000420323.7 link	c.4686-3C>T	splice_region_variant, intron_variant	Intron 28 of 77	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5 link	n.4947-3C>T	splice_region_variant, intron_variant	Intron 28 of 76	2
DNAH1	ENST00000466628.1 link	n.-58C>T	upstream_gene_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000436

AC:

AN:

229618

AF XY:

0.00000797

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000596

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.95e-7

AC:

AN:

1437824

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714040

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

32590

American (AMR)

AF:

0.00

AC:

AN:

40874

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24972

East Asian (EAS)

AF:

0.0000256

AC:

AN:

38996

South Asian (SAS)

AF:

0.00

AC:

AN:

82156

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52048

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101196

Other (OTH)

AF:

0.00

AC:

AN:

59330

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

8.8

(source)

DANN

Benign

0.71

PhyloP100

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00081

dbscSNV1_RF

Benign

0.12

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over