rs199603472

Positions:

• chr3-52394943-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_015512.5(DNAH1):​c.10852T>C​(p.Tyr3618His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,613,624 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.354

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059653223).
• BP6: Variant 3-52394943-T-C is Benign according to our data. Variant chr3-52394943-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 544665.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00108 (164/152328) while in subpopulation AFR AF= 0.00373 (155/41572). AF 95% confidence interval is 0.00325. There are 1 homozygotes in gnomad4. There are 70 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.10852T>C	p.Tyr3618His	missense_variant	68/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.10921T>C	p.Tyr3641His	missense_variant	70/80		XP_016861618.1
DNAH1	XM_017006130.2	c.10852T>C	p.Tyr3618His	missense_variant	69/79		XP_016861619.1
DNAH1	XM_017006131.2	c.10795T>C	p.Tyr3599His	missense_variant	69/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.10852T>C	p.Tyr3618His	missense_variant	68/78	1	NM_015512.5	ENSP00000401514	P1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 165 AN: 152210 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00376

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000185 AC: 46 AN: 248020 Hom.: 0 AF XY: 0.000134 AC XY: 18 AN XY: 134668

Gnomad AFR exome AF: 0.00254

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000117 AC: 171 AN: 1461296 Hom.: 1 Cov.: 32 AF XY: 0.000102 AC XY: 74 AN XY: 726890

Gnomad4 AFR exome AF: 0.00406

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152328 Hom.: 1 Cov.: 32 AF XY: 0.000940 AC XY: 70 AN XY: 74488

Gnomad4 AFR AF: 0.00373

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000191 Hom.: 0

Bravo AF: 0.00121

ESP6500AA AF: 0.00292 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000248 AC: 30

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

The c.10852T>C (p.Y3618H) alteration is located in exon 68 (coding exon 67) of the DNAH1 gene. This alteration results from a T to C substitution at nucleotide position 10852, causing the tyrosine (Y) at amino acid position 3618 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

- -

DNAH1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2024

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
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	14
DANN	Benign	0.93
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.023
Sift	Benign	0.15	T
Sift4G	Uncertain	0.056	T
Vest4		0.20
MVP		0.092
MPC		0.16
ClinPred		0.0041	T
GERP RS		-1.4
gMVP		0.35

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: rs199603472; hg19: chr3-52428959;