rs376991251

Variant names:

• chr3-52347854-C-T
• rs376991251
• NM_015512.5:c.1986C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-52347854-C-T
• chr3-52347854-C-A
• chr3-52347854-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_015512.5(DNAH1):​c.1986C>T​(p.Asp662Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,600,494 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (22 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.574
• Publications: 0 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 3-52347854-C-T is Benign according to our data. Variant chr3-52347854-C-T is described in ClinVar as Benign. ClinVar VariationId is 478422.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.574 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00106 (161/152304) while in subpopulation SAS AF = 0.0135 (65/4830). AF 95% confidence interval is 0.0108. There are 0 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 22 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.1986C>T	p.Asp662Asp	synonymous	Exon 12 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.1986C>T	p.Asp662Asp	synonymous	Exon 12 of 78	ENSP00000401514.2	Q9P2D7-4
	DNAH1	ENST00000486752.5	TSL:2	n.2247C>T		non_coding_transcript_exon	Exon 12 of 77
	DNAH1	ENST00000497875.1	TSL:2	n.2151C>T		non_coding_transcript_exon	Exon 13 of 21

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0134

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00231 AC: 529 AN: 229476 AF XY: 0.00304

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000248

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000488

Gnomad NFE exome AF: 0.00140

Gnomad OTH exome AF: 0.00106

GnomAD4 exome AF: 0.00154 AC: 2237 AN: 1448190 Hom.: 22 Cov.: 31 AF XY: 0.00194 AC XY: 1391 AN XY: 718790

African (AFR) AF: 0.0000602 AC: 2 AN: 33208

American (AMR) AF: 0.000350 AC: 15 AN: 42888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25766

East Asian (EAS) AF: 0.00 AC: 0 AN: 39168

South Asian (SAS) AF: 0.0135 AC: 1134 AN: 83950

European-Finnish (FIN) AF: 0.000398 AC: 21 AN: 52706

Middle Eastern (MID) AF: 0.00488 AC: 28 AN: 5742

European-Non Finnish (NFE) AF: 0.000834 AC: 922 AN: 1104952

Other (OTH) AF: 0.00192 AC: 115 AN: 59810

GnomAD4 genome AF: 0.00106 AC: 161 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.00128 AC XY: 95 AN XY: 74478

African (AFR) AF: 0.0000481 AC: 2 AN: 41574

American (AMR) AF: 0.000785 AC: 12 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

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

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4830

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68016

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000808 Hom.: 0

Bravo AF: 0.000805

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.3
DANN	Benign	0.89
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs376991251; hg19: chr3-52381870;