rs534534857

Variant names:

• chr3-52353585-C-T
• rs534534857
• NM_015512.5:c.3432C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP7 BS1_Supporting

The NM_015512.5(DNAH1):​c.3432C>T​(p.Ser1144Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,611,612 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• Conservation: PhyloP100: -0.325

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP7: Synonymous conserved (PhyloP=-0.325 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00021 (306/1459264) while in subpopulation MID AF= 0.00312 (18/5766). AF 95% confidence interval is 0.00202. There are 1 homozygotes in gnomad4_exome. There are 173 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.3432C>T	p.Ser1144Ser	synonymous_variant	Exon 20 of 78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.3432C>T	p.Ser1144Ser	synonymous_variant	Exon 21 of 80		XP_016861618.1
DNAH1	XM_017006130.2	c.3432C>T	p.Ser1144Ser	synonymous_variant	Exon 21 of 79		XP_016861619.1
DNAH1	XM_017006131.2	c.3432C>T	p.Ser1144Ser	synonymous_variant	Exon 21 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.3432C>T	p.Ser1144Ser	synonymous_variant	Exon 20 of 78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5	n.3693C>T		non_coding_transcript_exon_variant	Exon 20 of 77	2
DNAH1	ENST00000497875.1	n.3597C>T		non_coding_transcript_exon_variant	Exon 21 of 21	2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000229 AC: 56 AN: 244040 Hom.: 0 AF XY: 0.000234 AC XY: 31 AN XY: 132506

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000471

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000400

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000217

Gnomad OTH exome AF: 0.000676

GnomAD4 exome AF: 0.000210 AC: 306 AN: 1459264 Hom.: 1 Cov.: 31 AF XY: 0.000238 AC XY: 173 AN XY: 725754

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000586

Gnomad4 ASJ exome AF: 0.0000768

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000466

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000190

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74492

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000162

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: c.3431_3432delinsAT (p.Ser1144Asn). Missense variant, not reported previously. -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

DNAH1-related disorder Benign:1

Aug 27, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	7.0
DANN	Benign	0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs534534857; hg19: chr3-52387601;