7-1744672-C-T

Variant names:

• chr7-1744672-C-T
• rs370941771
• NM_001128636.4:c.76C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001128636.4(ELFN1):​c.76C>T​(p.Arg26Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00318 in 1,550,932 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R26H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (12 hom.)
• Consequence: ELFN1 NM_001128636.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.88
• Publications: 3 publications found

Genes affected

ELFN1 (HGNC:33154): (extracellular leucine rich repeat and fibronectin type III domain containing 1) Predicted to enable protein phosphatase inhibitor activity. Predicted to be involved in synapse organization. Predicted to be located in dendrite and excitatory synapse. Predicted to be active in extracellular matrix and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01801309).
• BP6: Variant 7-1744672-C-T is Benign according to our data. Variant chr7-1744672-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 723258.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128636.4. 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
	ELFN1	NM_001128636.4	MANE Select	c.76C>T	p.Arg26Cys	missense	Exon 4 of 4	NP_001122108.1	P0C7U0
	ELFN1	NM_001394187.1		c.76C>T	p.Arg26Cys	missense	Exon 3 of 3	NP_001381116.1	P0C7U0
	ELFN1	NM_001394188.1		c.76C>T	p.Arg26Cys	missense	Exon 4 of 4	NP_001381117.1	P0C7U0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELFN1	ENST00000424383.5	TSL:5 MANE Select	c.76C>T	p.Arg26Cys	missense	Exon 4 of 4	ENSP00000456548.1	P0C7U0
	ELFN1	ENST00000561626.4	TSL:2	c.76C>T	p.Arg26Cys	missense	Exon 3 of 3	ENSP00000457193.1	P0C7U0
	ELFN1	ENST00000691883.1		c.76C>T	p.Arg26Cys	missense	Exon 3 of 3	ENSP00000510296.1	P0C7U0

Frequencies

GnomAD3 genomes AF: 0.00213 AC: 324 AN: 151942 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000629

Gnomad AMI AF: 0.00442

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00399

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00165 AC: 255 AN: 154900 AF XY: 0.00164

Gnomad AFR exome AF: 0.000252

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00104

Gnomad NFE exome AF: 0.00378

Gnomad OTH exome AF: 0.00160

GnomAD4 exome AF: 0.00330 AC: 4611 AN: 1398874 Hom.: 12 Cov.: 31 AF XY: 0.00321 AC XY: 2217 AN XY: 690000

African (AFR) AF: 0.000412 AC: 13 AN: 31590

American (AMR) AF: 0.000168 AC: 6 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.000199 AC: 5 AN: 25166

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35730

South Asian (SAS) AF: 0.0000505 AC: 4 AN: 79226

European-Finnish (FIN) AF: 0.00174 AC: 85 AN: 48906

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5698

European-Non Finnish (NFE) AF: 0.00408 AC: 4401 AN: 1078880

Other (OTH) AF: 0.00160 AC: 93 AN: 57984

GnomAD4 genome AF: 0.00213 AC: 324 AN: 152058 Hom.: 2 Cov.: 33 AF XY: 0.00207 AC XY: 154 AN XY: 74314

African (AFR) AF: 0.000627 AC: 26 AN: 41482

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10606

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00399 AC: 271 AN: 67952

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00257 Hom.: 0

Bravo AF: 0.00175

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00440 AC: 14

ExAC AF: 0.000674 AC: 40

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ELFN1-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.089	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.018	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.0	D
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.95	P
Vest4		0.33
MVP		0.51
MPC		0.78
GERP RS		4.2
Varity_R		0.17
gMVP		0.43
Mutation Taster		=89/11	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: rs370941771; hg19: chr7-1784308; COSMIC: COSV70033787; COSMIC: COSV70033787;