rs114066123

Variant names:

• chr3-52353276-C-T
• rs114066123
• NM_015512.5:c.3201C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-52353276-C-T
• chr3-52353276-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015512.5(DNAH1):​c.3201C>T​(p.Cys1067Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00955 in 1,613,862 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0098 (105 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.19
• Publications: 4 publications found

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: Labcorp Genetics (formerly Invitae), ClinGen
• ciliary dyskinesia, primary, 37

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 3-52353276-C-T is Benign according to our data. Variant chr3-52353276-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 478439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00719 (1095/152316) while in subpopulation NFE AF = 0.0114 (779/68036). AF 95% confidence interval is 0.0108. There are 7 homozygotes in GnomAd4. There are 546 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015512.5. 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
	DNAH1	NM_015512.5	MANE Select	c.3201C>T	p.Cys1067Cys	synonymous	Exon 19 of 78	NP_056327.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	ENST00000420323.7	TSL:1 MANE Select	c.3201C>T	p.Cys1067Cys	synonymous	Exon 19 of 78	ENSP00000401514.2	Q9P2D7-4
	DNAH1	ENST00000486752.5	TSL:2	n.3462C>T		non_coding_transcript_exon	Exon 19 of 77
	DNAH1	ENST00000497875.1	TSL:2	n.3366C>T		non_coding_transcript_exon	Exon 20 of 21

Frequencies

GnomAD3 genomes AF: 0.00720 AC: 1096 AN: 152198 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00866 AC: 2153 AN: 248712 AF XY: 0.00882

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0177

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.00844

GnomAD4 exome AF: 0.00980 AC: 14324 AN: 1461546 Hom.: 105 Cov.: 31 AF XY: 0.00952 AC XY: 6924 AN XY: 727054

African (AFR) AF: 0.00122 AC: 41 AN: 33480

American (AMR) AF: 0.00210 AC: 94 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00130 AC: 34 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.0196 AC: 1045 AN: 53324

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.0113 AC: 12618 AN: 1111810

Other (OTH) AF: 0.00802 AC: 484 AN: 60370

GnomAD4 genome AF: 0.00719 AC: 1095 AN: 152316 Hom.: 7 Cov.: 33 AF XY: 0.00733 AC XY: 546 AN XY: 74482

African (AFR) AF: 0.00183 AC: 76 AN: 41552

American (AMR) AF: 0.00444 AC: 68 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0148 AC: 157 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0114 AC: 779 AN: 68036

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00869 Hom.: 0

Bravo AF: 0.00563

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00872

EpiControl AF: 0.0104

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.53
DANN	Benign	0.59
PhyloP100		-1.2
Mutation Taster		=100/0	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: rs114066123; hg19: chr3-52387292;