rs186370335

Variant names:

• chr5-141573818-G-A
• rs186370335
• NM_005219.5:c.2032C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_005219.5(DIAPH1):​c.2032C>T​(p.Pro678Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,518,218 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 23)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.48
• Publications: 8 publications found

Genes affected

DIAPH1 (HGNC:2876): (diaphanous related formin 1) This gene is a homolog of the Drosophila diaphanous gene, and has been linked to autosomal dominant, fully penetrant, nonsyndromic sensorineural progressive low-frequency hearing loss. Actin polymerization involves proteins known to interact with diaphanous protein in Drosophila and mouse. It has therefore been speculated that this gene may have a role in the regulation of actin polymerization in hair cells of the inner ear. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

DIAPH1 Gene-Disease associations (from GenCC):

• DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• autosomal dominant nonsyndromic hearing loss 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010555029).
• BP6: Variant 5-141573818-G-A is Benign according to our data. Variant chr5-141573818-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 351290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000323 (48/148604) while in subpopulation EAS AF = 0.00742 (37/4984). AF 95% confidence interval is 0.00554. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005219.5. 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
	DIAPH1	NM_005219.5	MANE Select	c.2032C>T	p.Pro678Ser	missense	Exon 16 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.2005C>T	p.Pro669Ser	missense	Exon 15 of 27	NP_001073280.1
	DIAPH1	NM_001314007.2		c.2032C>T	p.Pro678Ser	missense	Exon 16 of 29	NP_001300936.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH1	ENST00000389054.8	TSL:5 MANE Select	c.2032C>T	p.Pro678Ser	missense	Exon 16 of 28	ENSP00000373706.4
	DIAPH1	ENST00000518047.5	TSL:5	c.2005C>T	p.Pro669Ser	missense	Exon 15 of 27	ENSP00000428268.2
	DIAPH1	ENST00000647433.1		c.2032C>T	p.Pro678Ser	missense	Exon 16 of 29	ENSP00000494675.1

Frequencies

GnomAD3 genomes AF: 0.000323 AC: 48 AN: 148500 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00740

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000493

GnomAD2 exomes AF: 0.000735 AC: 103 AN: 140102 AF XY: 0.000796

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00782

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000518

GnomAD4 exome AF: 0.000181 AC: 248 AN: 1369614 Hom.: 1 Cov.: 35 AF XY: 0.000179 AC XY: 120 AN XY: 670722

African (AFR) AF: 0.0000312 AC: 1 AN: 32056

American (AMR) AF: 0.0000577 AC: 2 AN: 34650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21912

East Asian (EAS) AF: 0.00491 AC: 182 AN: 37052

South Asian (SAS) AF: 0.000180 AC: 13 AN: 72034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5506

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1061280

Other (OTH) AF: 0.000844 AC: 48 AN: 56870

GnomAD4 genome AF: 0.000323 AC: 48 AN: 148604 Hom.: 0 Cov.: 23 AF XY: 0.000387 AC XY: 28 AN XY: 72390

African (AFR) AF: 0.000248 AC: 10 AN: 40312

American (AMR) AF: 0.00 AC: 0 AN: 14926

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.00742 AC: 37 AN: 4984

South Asian (SAS) AF: 0.00 AC: 0 AN: 4556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66854

Other (OTH) AF: 0.000488 AC: 1 AN: 2050

Alfa AF: 0.000522 Hom.: 1

Bravo AF: 0.000408

ExAC AF: 0.000376 AC: 44

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 1 (1)
-	-	1	Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (1)
-	-	1	DIAPH1-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.48
Sift	Benign	0.34	T
Sift4G	Uncertain	0.022	D
Polyphen		0.99	D
Vest4		0.39
MVP		0.88
MPC		0.12
ClinPred		0.085	T
GERP RS		3.7
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.2
Varity_R		0.058
gMVP		0.20
Mutation Taster		=53/47	polymorphism

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: rs186370335; hg19: chr5-140953385;