rs73072968

Variant names:

• chr3-52380096-C-T
• rs73072968
• NM_015512.5:c.7569C>T

Variant summary

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

The ENST00000420323.7(DNAH1):​c.7569C>T​(p.Ser2523Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,604,444 control chromosomes in the GnomAD database, including 378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (25 hom., cov: 32)
  • Exomes 𝑓: 0.020 (353 hom.)
• Consequence: DNAH1 ENST00000420323.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.722
• Publications: 7 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: 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 3-52380096-C-T is Benign according to our data. Variant chr3-52380096-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 478493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.722 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0159 (2420/152248) while in subpopulation AMR AF = 0.0235 (359/15302). AF 95% confidence interval is 0.0219. There are 25 homozygotes in GnomAd4. There are 1153 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000420323.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	NM_015512.5	MANE Select	c.7569C>T	p.Ser2523Ser	synonymous	Exon 48 of 78	NP_056327.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	ENST00000420323.7	TSL:1 MANE Select	c.7569C>T	p.Ser2523Ser	synonymous	Exon 48 of 78	ENSP00000401514.2
	DNAH1	ENST00000486752.5	TSL:2	n.7830C>T		non_coding_transcript_exon	Exon 48 of 77

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2419 AN: 152130 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00374

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0235

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0237

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0156 AC: 3625 AN: 231986 AF XY: 0.0157

Gnomad AFR exome AF: 0.00310

Gnomad AMR exome AF: 0.0181

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0218

Gnomad NFE exome AF: 0.0220

Gnomad OTH exome AF: 0.0192

GnomAD4 exome AF: 0.0200 AC: 29024 AN: 1452196 Hom.: 353 Cov.: 31 AF XY: 0.0196 AC XY: 14113 AN XY: 721416

African (AFR) AF: 0.00429 AC: 143 AN: 33306

American (AMR) AF: 0.0184 AC: 798 AN: 43450

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 291 AN: 25906

East Asian (EAS) AF: 0.0000509 AC: 2 AN: 39290

South Asian (SAS) AF: 0.00150 AC: 126 AN: 84190

European-Finnish (FIN) AF: 0.0212 AC: 1120 AN: 52718

Middle Eastern (MID) AF: 0.0158 AC: 91 AN: 5758

European-Non Finnish (NFE) AF: 0.0229 AC: 25366 AN: 1107540

Other (OTH) AF: 0.0181 AC: 1087 AN: 60038

GnomAD4 genome AF: 0.0159 AC: 2420 AN: 152248 Hom.: 25 Cov.: 32 AF XY: 0.0155 AC XY: 1153 AN XY: 74454

African (AFR) AF: 0.00375 AC: 156 AN: 41546

American (AMR) AF: 0.0235 AC: 359 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.0237 AC: 252 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0228 AC: 1551 AN: 68004

Other (OTH) AF: 0.0242 AC: 51 AN: 2110

Alfa AF: 0.0199 Hom.: 40

Bravo AF: 0.0161

Asia WGS AF: 0.00202 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.63
CADD	Benign	2.3
DANN	Benign	0.58
PhyloP100		-0.72
Mutation Taster		=99/1	polymorphism (auto)

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: rs73072968; hg19: chr3-52414112;