rs367669306

Variant names:

• chr5-141573886-G-C
• rs367669306
• NM_005219.5:c.1964C>G

Your query was ambiguous. Multiple possible variants found:

• chr5-141573886-G-C
• chr5-141573886-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005219.5(DIAPH1):​c.1964C>G​(p.Pro655Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000568 in 1,545,202 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P655A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00060 (10 hom.)
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 8.93
• Publications: 0 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: Orphanet, ClinGen
• progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• autosomal dominant nonsyndromic hearing loss 1

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009348184).
• BP6: Variant 5-141573886-G-C is Benign according to our data. Variant chr5-141573886-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 542368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000291 (44/151448) while in subpopulation SAS AF = 0.00755 (36/4770). AF 95% confidence interval is 0.0056. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH1	NM_005219.5	MANE Select	c.1964C>G	p.Pro655Arg	missense	Exon 16 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.1937C>G	p.Pro646Arg	missense	Exon 15 of 27	NP_001073280.1	O60610-3
	DIAPH1	NM_001314007.2		c.1964C>G	p.Pro655Arg	missense	Exon 16 of 29	NP_001300936.1	A0A2R8Y5N1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH1	ENST00000389054.8	TSL:5 MANE Select	c.1964C>G	p.Pro655Arg	missense	Exon 16 of 28	ENSP00000373706.4	O60610-1
	DIAPH1	ENST00000518047.5	TSL:5	c.1937C>G	p.Pro646Arg	missense	Exon 15 of 27	ENSP00000428268.2	O60610-3
	DIAPH1	ENST00000647433.1		c.1964C>G	p.Pro655Arg	missense	Exon 16 of 29	ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes AF: 0.000297 AC: 45 AN: 151338 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00775

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00147 AC: 221 AN: 149862 AF XY: 0.00200

Gnomad AFR exome AF: 0.000239

Gnomad AMR exome AF: 0.0000410

Gnomad ASJ exome AF: 0.000683

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.00119

GnomAD4 exome AF: 0.000598 AC: 833 AN: 1393754 Hom.: 10 Cov.: 37 AF XY: 0.000835 AC XY: 573 AN XY: 686390

African (AFR) AF: 0.0000626 AC: 2 AN: 31964

American (AMR) AF: 0.0000283 AC: 1 AN: 35382

Ashkenazi Jewish (ASJ) AF: 0.000167 AC: 4 AN: 24022

East Asian (EAS) AF: 0.00 AC: 0 AN: 36338

South Asian (SAS) AF: 0.00947 AC: 731 AN: 77182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48704

Middle Eastern (MID) AF: 0.00390 AC: 22 AN: 5642

European-Non Finnish (NFE) AF: 0.0000139 AC: 15 AN: 1076662

Other (OTH) AF: 0.00100 AC: 58 AN: 57858

GnomAD4 genome AF: 0.000291 AC: 44 AN: 151448 Hom.: 0 Cov.: 26 AF XY: 0.000406 AC XY: 30 AN XY: 73960

African (AFR) AF: 0.000170 AC: 7 AN: 41244

American (AMR) AF: 0.00 AC: 0 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00755 AC: 36 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67760

Other (OTH) AF: 0.00 AC: 0 AN: 2096

Alfa AF: 0.000528 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.000852 AC: 94

Asia WGS AF: 0.00664 AC: 23 AN: 3478

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0093	T
MetaSVM	Uncertain	0.029	D
MutationAssessor	Benign	1.8	L
PhyloP100		8.9
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.56		Loss of glycosylation at P655 (P = 0.0029)
MVP		0.95
MPC		0.12
ClinPred		0.061	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.28
Mutation Taster		=90/10	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: rs367669306; hg19: chr5-140953453;