3-52358002-G-T

Position:

• chr3-52358002-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015512.5(DNAH1):​c.4085G>T​(p.Arg1362Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,601,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. R1362R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: DNAH1 NM_015512.5 missense, splice_region
• Scores: Splicing: ADA: 0.02613
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.380

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 (MetaRNN=0.022660226).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.4085G>T	p.Arg1362Leu	missense_variant, splice_region_variant	24/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.4085G>T	p.Arg1362Leu	missense_variant, splice_region_variant	25/80
DNAH1	XM_017006130.2	c.4085G>T	p.Arg1362Leu	missense_variant, splice_region_variant	25/79
DNAH1	XM_017006131.2	c.4085G>T	p.Arg1362Leu	missense_variant, splice_region_variant	25/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.4085G>T	p.Arg1362Leu	missense_variant, splice_region_variant	24/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.4346G>T		splice_region_variant, non_coding_transcript_exon_variant	24/77	2

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000406 AC: 98 AN: 241096 Hom.: 0 AF XY: 0.000426 AC XY: 56 AN XY: 131444

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000599

Gnomad ASJ exome AF: 0.00809

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000165

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000242 AC: 350 AN: 1449124 Hom.: 0 Cov.: 32 AF XY: 0.000267 AC XY: 192 AN XY: 718986

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.0000229

Gnomad4 ASJ exome AF: 0.00897

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000734

Gnomad4 OTH exome AF: 0.000535

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74496

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000430 Hom.: 0

Bravo AF: 0.000242

ExAC AF: 0.000290 AC: 35

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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: At least 1 variant in this gene has been reported in a PCD patient, however the only LOF variants in HGMD caused sperm motility defects without respiratory phenotype. Potential impact to splicing, but no other suspicious variants in this gene. -OB 10/21/15: VUS4. Limited evidence on whether the gene is related to disease and unclear whether it is associated with pulmonary phenotype. Heterozygous variant in recessive gene. Does not meet criteria for reporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Uncertain	1.0
Eigen	Benign	-0.027
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.31
Sift	Benign	0.044	D
Sift4G	Uncertain	0.049	D
Vest4		0.66
MVP		0.46
MPC		0.24
ClinPred		0.20	T
GERP RS		3.1
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.026
dbscSNV1_RF	Benign	0.19
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: rs201355893; hg19: chr3-52392018;